Amantadine compositions, preparations thereof, and methods of use

ABSTRACT

Provided herein are oral pharmaceutical compositions comprising amantadine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and which have a low level of organic solvent. Provided are also methods of orally administrating a composition comprising amantadine, or a pharmaceutically acceptable salt thereof, to a subject, which has reduced gastrointestinal side effects or sleep disturbances. Further provided are extended release oral compositions comprising amantadine, or a pharmaceutically acceptable salt thereof, that are suitable for once daily administration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/677,431, filed on Nov. 7, 2019, which is a divisional of U.S. patentapplication Ser. No. 16/409,554, filed on May 10, 2019, which is acontinuation application of International Application No.PCT/US2018/047754, filed on Aug. 23, 2018, which claims the benefit ofU.S. Provisional Application No. 62/549,921, filed on Aug. 24, 2017, thedisclosures of which are incorporated herein by reference in theirentireties.

FIELD

This disclosure generally relates to oral pharmaceutical compositionscomprising amantadine, or pharmaceutically acceptable salts thereof, andmore specifically relates to extended release oral pharmaceuticalcompositions comprising amantadine, or pharmaceutically acceptable saltsthereof, the preparation of such compositions, and methods of using suchcompositions.

BACKGROUND

Amantadine is indicated for various conditions that can be treated byNMDA receptor antagonists including the treatment of idiopathicParkinson's disease (Paralysis Agitans), post-encephalitic Parkinsonism,and symptomatic Parkinsonism which may follow injury to the nervoussystem by carbon monoxide intoxication. Amantadine also has activity asa viral M2 channel inhibitor and is used for the prophylaxis andtreatment of infection of viral diseases, especially influenza A virus.

Levodopa, the most commonly prescribed and effective drug treatment forsymptomatic relief in Parkinson's disease (PD) is associated withdose-limiting motor side-effects, including abnormal involuntarymovements known as levodopa-induced dyskinesia (LID). With continuedlevodopa treatment, and as PD progresses to moderate and severe stages,dyskinesias can become severely disabling and have been associated witha decrease in the quality of life. Encarnacion, E. V. and Hauser, R. A.,Levodopa-induced dyskinesias in Parkinson's disease: etiology, impact onquality of life, and treatments. Eur Neurol, 2008. 60(2): p. 57-66.There are currently no medications approved for the treatment of LID,thus there is a significant unmet medical need (as of August 2017).

LID may require a reduction in the levodopa dose causing patients toreceive sub-optimal PD treatment. The treatment of LID that becomesseverely disabling resulting in a decrease in the quality of life is anunmet medical need. Encarnacion et al., supra.

As of August 2018, the extended release formulation of amantadinehydrochloride GOCOVRI™ was the first and only medicine approved by theU.S. Food and Drug Administration (FDA) for the treatment of dyskinesiain people with Parkinson's disease receiving levodopa-based therapy,with or without concomitant dopaminergic medications. GOCOVRI™ is thefirst Parkinson's disease medicine proven in controlled trials to reduceboth dyskinesia and OFF time in Parkinson's disease patients receivinglevodopa.

Amantadine (amantadine) is a weak, non-competitive N-methyl d-aspartate(NMDA) receptor antagonist that promotes release of dopamine. Guttman,M., Kish, S. J., Furukawa, Y., Current concepts in the diagnosis andmanagement of Parkinson's disease. Cmaj, 2003. 168(3): p. 293-301.Amantadine has shown efficacy in animal models of LID and is usedoff-label by neurologists and movement disorder specialists to treat LIDin patients with PD. Blanchet, P. J., Konitsiotis, S., Chase, T. N.,Amantadine reduces levodopa-induced dyskinesias in parkinsonian monkeys.Mov Disord, 1998. 13(5): p. 798-802. Fox, S. H., Lang, A. E., Brotchie,J. M., Translation of non-dopaminergic treatments for levodopa-induceddyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinicalstudies: keys to success and roads to failure. Mov Disord, 2006. 21(10):p. 1578-94.

A number of small studies with different designs and outcome measures inPD patients have shown amantadine (IR formulation) to be effective inthe treatment of LID. At amantadine doses of 200 mg/day, anapproximately 25% reduction in LID was reported (da Silva-Junior, F. P.,Braga-Neto, P., Monte, F. S., et al., Amantadine reduces the duration oflevodopa-induced dyskinesia: a randomized, double-blind,placebo-controlled study. Parkinsonism Relat Disord, 2005. 11(7): p.449-52; Snow, B. J., Macdonald, L., Mcauley, D., et al., The effect ofamantadine on levodopa-induced dyskinesias in Parkinson's disease: adouble-blind, placebo-controlled study. Clin Neuropharmacol, 2000.23(2): p. 82-85) and at doses of 300 mg/day, the reduction of LID wasreported to be ˜40% (Luginger, E., Wenning, G. K., Bosch, S., et al.,Beneficial effects of amantadine on L-dopa-induced dyskinesias inParkinson's disease. Mov Disord, 2000. 15(5): p. 873-8; Paci, C.,Thomas, A., Onofrj, M., Amantadine for dyskinesia in patients affectedby severe Parkinson's disease. Neurol Sci, 2001. 22(1): p. 75-6; Thomas,A., Iacono, D., Luciano, A. L., et al., Duration of amantadine benefiton dyskinesia of severe Parkinson's disease. J Neurol NeurosurgPsychiatry, 2004. 75(1): p. 141-3.) In one study conducted at 300 to 400mg/day, the reduction was reported to be ˜60% (Metman, L. V., Del Dotto,P., Lepoole, K., et al., Amantadine for levodopa-induced dyskinesias: a1-year follow-up study. Arch Neurol, 1999. 56(11): p. 1383-6.) Ingeneral, the reduction in LID appears to increase with increasingamantadine dose.

Many marketed forms of amantadine are generally immediate releaseformulations that are typically administered two or more times a day.Amantadine's use is limited by dose related CNS side effects includingdizziness, confusion, hallucinations, insomnia and nightmares (Gracies JM, Olanow C W; Current and Experimental Therapeutics of Parkinson'sDisease; Neuropsychopharmacology: the Fifth Generation of Progress pp1802; American College of Neuropsychopharmacology 2002), which can beparticularly exacerbated when amantadine is administered late in the day(Jackson et al., Bull Pan Am Health Org, 147, 595-603 (1967)); Jackson,JAMA, 235(25), (1976), 2739-2742; Hayden, AAC, 19(2) 1981, pp. 226-233;and Hayden, AAC, 23(3) 1983, pp. 458-464).

Doses of 200 mg/day of amantadine (IR formulation) have been generallytolerated by the majority of PD patients. However, at this dose level,amantadine efficacy in LID is sub-optimal for many patients. Doses of300 mg/day or higher amantadine IR produce greater reduction in LIDsymptoms but are associated with central nervous system (CNS) sideeffects including hallucinations, insomnia, nausea and dizziness(lightheadedness) and gastrointestinal (GI) side effects including lossof appetite, nausea, vomiting, and diarrhea (Jackson et al., supra;Hayden, supra). In one study of immediate release amantadine, increasedplasma concentrations were associated with a higher incidence of CNS andsleep related side effects, but not with GI side effects (Hayden 1983,supra).

It is known that immediate release amantadine can act as a stimulant,causing insomnia and sleep disturbance. Therefore, the last dose istypically administered no later than 4 pm in order to minimize theseside effects (Fachinformation—Amantadin CT 100 mg Filmtabletten, March,2008; Fung et al, Aust. Prescriber, 24(4) 2001, pp 92-95). Such dosingof amantadine results in peak plasma amantadine concentrations occurringin the evening or night, and very low plasma concentrations in themorning.

Extended release forms of amantadine have been described in the art.U.S. Pat. No. 5,358,721, to Guittard et al., and U.S. Pat. No.6,217,905, to Edgren et al., each disclose an oral osmotic dosage formcomprising an antiviral or anti-Parkinson's drug, respectively, where ineach case amantadine is listed as a possible drug to be utilized in thedosage form. U.S. Pat. No. 6,194,000, to Smith et al., disclosesanalgesic immediate and controlled release pharmaceutical compositionsutilizing NMDA receptor antagonists, such as amantadine, as the activeagent. U.S. Patent Appl. Publication Nos. US 2006/0252788, US2006/0189694 (U.S. Pat. No. 8,389,578), US 2006/0142398, US2008/0227743, and US2011/0189273 (U.S. Pat. No. 8,741,343), all to Wentet al., each disclose the administration of an NMDA receptor antagonist,such as amantadine, optionally in controlled release form.

Recently, an extended release formulation of amantadine has been shownto reduce LID in Parkinson's patients taking levodopa (Pahwa et al.Amantadine Extended Release for Levodopa-Induced Dyskinesia inParkinson's Disease (EASED Study), Mov Disord. 2015. 30(6):788-795).These extended release compositions are administered once nightly at 260to 420 mg without increasing sleep related adverse effects(US20110189273, US20150087721, Pahwa et al., supra). Immediate releaseforms of amantadine have been used to treat fatigue in patients withMultiple Sclerosis. Recently, extended release compositions have beeninvestigated for treating hypokinetic movement disorders in patientswith Multiple Sclerosis (US2016/0228388). As discussed above, theextended release formulation of amantadine hydrochloride GOCOVRI™ wasrecently approved by the FDA as the first and only medicine approved bythe FDA for the treatment of dyskinesia in people with Parkinson'sdisease receiving levodopa-based therapy, with or without concomitantdopaminergic medications. GOCOVRI™ is the first Parkinson's diseasemedicine proven in controlled trials to reduce both dyskinesia and OFFtime in Parkinson's disease patients receiving levodopa.

However, gastrointestinal side effects associated with administration ofimmediate release and known extended release amantadine formulationsremain a significant issue; thus, improved compositions and methods areneeded.

SUMMARY

Described herein are extended release oral compositions comprisingamantadine, or a pharmaceutically acceptable salt thereof, and methodsof administering amantadine, or a pharmaceutically acceptable saltthereof (such as amantadine hydrochloride), which provide improvedgastrointestinal adverse event rates over the known formulations. Thecompositions of the present disclosure also provide improvedgastrointestinal adverse events rates over the previously describedextended release formulations. When these extended release oralcompositions are administered at an amantadine dose of 50 mg to 500 mg,or an equivalent amount of a pharmaceutically acceptable salt thereof,once nightly to a subject Parkinson's disease the compositions are welltolerated and provide improvements in Parkinson's symptoms, motorfluctuations, levodopa induced dyskinesia (LID), and provides animprovement in physician's Clinical Global Impression of Change (CGIC).The effectiveness measures for once nightly administration of theamantadine oral compositions described herein are superior to currentlyavailable formulations of amantadine, e.g., immediate release formsadministered in divided doses. Additionally, the compositions of thepresent disclosure provide improved tolerability relative to knownformulations, particularly when administered once daily and especiallywhen administered once daily 0 to 4 hours before bedtime.

The present disclosure, in some aspects, provides an extended releaseoral composition comprising 50 mg to 500 mg, 60 mg to 400 mg, 60 mg to300 mg, 137 mg to 500 mg, preferably 260 mg to 420 mg, of amantadine ora pharmaceutically acceptable salt thereof in the form of a compositiondescribed herein, and upon administration to subjects of a single dose,fasting human pharmacokinetic study provides a low incidence ofgastrointestinal side effects including one or more of the followinggastrointestinal disorders: abdominal distension, constipation,diarrhea, dyspepsia, gingival pain, dry lip, lower abdominal pain,nausea, stomach discomfort, toothache, upper abdominal pain, andvomiting. In some variations, the extended release oral compositioncomprises less than 6000 ppm organic solvent, for example less than 5500ppm, less than 5000 ppm, less than 4500 ppm, less than 4000 ppm, lessthan 3500 ppm, less than 3000 ppm, less than 2500 ppm, less than 2000ppm, less than 1500 ppm, or less than 1200 ppm organic solvent. Incertain embodiments, the extended release oral composition comprises aplurality of core seeds, wherein each core seed is surrounded by a drugcoating, and the plurality of coated core seeds comprises less than 6000ppm, less than 5500 ppm, less than 5000 ppm, less than 4500 ppm, lessthan 4000 ppm, less than 3500 ppm, less than 3000 ppm, less than 2500ppm, less than 2000 ppm, less than 1500 ppm, or less than 1200 ppmorganic solvent. In some embodiments, the extended release oralcomposition comprises about 68.5 mg, about 137 mg, about 205.5 mg, orabout 274 mg of amantadine. In certain embodiments, the extended releaseoral composition comprises from about 60 mg to about 80 mg, from about120 mg to about 155 mg, from about 185 mg to about 230 mg, or from about245 mg to about 305 mg of amantadine. In some embodiments, the extendedrelease oral composition comprises about 85 mg, about 170 mg, about 255mg, or about 340 mg of amantadine hydrochloride. In certain embodiments,the extended release oral composition comprises from about 75 mg toabout 95 mg, from about 150 mg to about 190 mg, from about 230 mg toabout 285 mg, or from about 305 to about 375 mg of amantadinehydrochloride.

In a second aspect, the disclosure provides a method of administering anextended release oral composition comprising 50 mg to 500 mg, 60 mg to400 mg, 60 mg to 300 mg, 137 mg to 500 mg, preferably 260 mg to 420 mg,of amantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof, to a human subject once daily, wherein the extendedrelease oral composition is therapeutically effective for treatment ofsaid subject and wherein the extended release oral composition has a lowincidence of one or more of the aforementioned gastrointestinal sideeffects when administered to subjects of a fasted, single dose humanpharmacokinetic study. In some embodiments, the single dose, fastedhuman pharmacokinetic study is dosed in the morning following anovernight fast. In some variations, the extended release oralcomposition comprises less than 6000 ppm organic solvent, for exampleless than 5500 ppm, less than 5000 ppm, less than 4500 ppm, less than4000 ppm, less than 3500 ppm, less than 3000 ppm, less than 2500 ppm,less than 2000 ppm, less than 1500 ppm, or less than 1200 ppm organicsolvent. In certain embodiments, the extended release oral compositioncomprises a plurality of core seeds, wherein each core seed issurrounded by a drug coating, and the plurality of coated core seedscomprises less than 6000 ppm, less than 5500 ppm, less than 5000 ppm,less than 4500 ppm, less than 4000 ppm, less than 3500 ppm, less than3000 ppm, less than 2500 ppm, less than 2000 ppm, less than 1500 ppm, orless than 1200 ppm organic solvent. In some embodiments, the extendedrelease oral composition comprises about 68.5 mg, about 137 mg, about205.5 mg, or about 274 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In certain embodiments, theextended release oral composition comprises from about 60 mg to about 80mg, from about 120 mg to about 155 mg, from about 185 mg to about 230mg, or from about 245 mg to about 305 mg of amantadine, or an equivalentamount of a pharmaceutically acceptable salt thereof. In someembodiments, the extended release oral composition comprises about 85mg, about 170 mg, about 255 mg, or about 340 mg of amantadinehydrochloride. In certain embodiments, the extended release oralcomposition comprises from about 75 mg to about 95 mg, from about 150 mgto about 190 mg, from about 230 mg to about 285 mg, or from about 305 toabout 375 mg of amantadine hydrochloride.

In a third aspect, the disclosure provides a method of administering anextended release oral composition comprising 50 mg to 500 mg, 60 mg to400 mg, 60 mg to 300 mg, 137 mg to 500 mg, preferably 260 mg to 420 mg,of amantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof, to a human subject once daily, 0 to 4 hours beforebedtime, wherein the extended release oral composition istherapeutically effective for treatment of said subject and wherein theextended release oral composition has a low incidence of one or more ofthe aforementioned gastrointestinal side effects when administered tosubjects of a fasted, single dose human pharmacokinetic study. In someembodiments, the extended release oral composition comprises about 68.5mg, about 137 mg, about 205.5 mg, or about 274 mg of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. Incertain embodiments, the extended release oral composition comprisesfrom about 60 mg to about 80 mg, from about 120 mg to about 155 mg, fromabout 185 mg to about 230 mg, or from about 245 mg to about 305 mg ofamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof. In some embodiments, the extended release oral compositioncomprises about 85 mg, about 170 mg, about 255 mg, or about 340 mg ofamantadine hydrochloride. In certain embodiments, the extended releaseoral composition comprises from about 75 mg to about 95 mg, from about150 mg to about 190 mg, from about 230 mg to about 285 mg, or from about305 to about 375 mg of amantadine hydrochloride.

In some embodiments of any of the aspects described herein, the extendedrelease oral composition has a low incidence of sleep related adverseeffects when administered to subjects of a fasted, single dose humanpharmacokinetic study. In some embodiments of any of the aspectsdescribed herein, the extended release oral composition has a lowincidence of sleep related adverse effects when administered at atherapeutically effective dose to subjects of a fasted, single dosehuman pharmacokinetic study. In some embodiments of any of the aspectsdescribed herein, the extended release oral composition has a lowincidence of gastrointestinal adverse events when administered tosubject of a fasted, single dose human pharmacokinetic study. In otherembodiments of any of the aspects described herein, the extended releaseoral composition has a low incidence of both sleep related adverseevents and gastrointestinal adverse events when administered at atherapeutically effective dose to subjects of a fasted, single dosehuman pharmacokinetic study. In some embodiments, a low incidence ofgastrointestinal adverse events includes less than 12%, less than 10%,less than 8%, less than 7%, less than 6%, less than 5%, less than 4%,less than 3%, less than 2%, or less than 1% of the subjects of a fasted,single dose human pharmacokinetic study experiencing at least onegastrointestinal adverse event.

In some aspects of the disclosure, amantadine, or an equivalent amountof a pharmaceutically acceptable salt thereof (such as thehydrochloride), in the form of a composition described herein, isadministered at 50 mg to 500 mg, 60 mg to 400 mg, 60 mg to 300 mg, 137mg to 500 mg, preferably 209 mg to 339 mg once nightly, 0 to 4 hoursbefore bedtime without sleep related adverse effects in a subject withParkinson's disease, and one (or more) of the following: A. LID in thesubject is significantly improved; B. the PD symptoms are improved; C.the Clinical Global Impression of Change is significantly improved(relative to placebo); and/or D. the Clinical Global Impression ofChange is significant, whereas higher and lower doses are notsignificantly different from placebo. In some aspects of the disclosure,the dyskinesia metrics in A can be from UDysRS or some of other form ofmetrics, infra. In some embodiments, the extended release oralcomposition comprises about 68.5 mg, about 137 mg, about 205.5 mg, orabout 274 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In certain embodiments, theextended release oral composition comprises from about 60 mg to about 80mg, from about 120 mg to about 155 mg, from about 185 mg to about 230mg, or from about 245 mg to about 305 mg of amantadine, or an equivalentamount of a pharmaceutically acceptable salt thereof. In someembodiments, the extended release oral composition comprises about 85mg, about 170 mg, about 255 mg, or about 340 mg of amantadinehydrochloride. In certain embodiments, the extended release oralcomposition comprises from about 75 mg to about 95 mg, from about 150 mgto about 190 mg, from about 230 mg to about 285 mg, or from about 305 toabout 375 mg of amantadine hydrochloride. In some embodiments, theamantadine is administered as amantadine hydrochloride at 260 mg to 420mg. In certain embodiments, 340 mg amantadine hydrochloride isadministered (i.e. equivalent to 274 mg amantadine).

In some aspects of the disclosure, amantadine, or an equivalent amountof a pharmaceutically acceptable salt thereof (such as thehydrochloride), in the form of a composition described herein, isadministered at 50 mg to 500 mg, 60 mg to 400 mg, 60 mg to 300 mg, 137mg to 500 mg, preferably 260 mg to 420 mg (more preferably 340 mg) oncenightly, 0 to 4 hours before bedtime to a subject with Parkinson'sdisease, resulting in one or more of the following: A. the daily ON timewithout troublesome dyskinesia is increased relative to placebo; B. thedaily ON time without dyskinesia is increased relative to placebo; C.the daily ON time with dyskinesia is decreased relative to placebo (orin a dose responsive manner); D. the daily ON time with troublesomedyskinesia is decreased relative to placebo (or in a dose responsivemanner); and/or E. the daily OFF time is decreased relative to placeboand/or higher amantadine dosage strengths. Thus, in some embodiments,administration of this drug once nightly before bedtime provides markedimprovement on following day measurements of efficacy (e.g., increase inON time without dyskinesia, decrease in OFF time, improvement indyskinesia) and/or tolerability. There is a need in the art for improvedformulations, and methods of treatment with such formulations, ofamantadine (or a pharmaceutically acceptable salt thereof) that resultin a subject having higher plasma concentrations of amantadine uponwaking in the morning with low incidence of gastrointestinal sideeffects and, preferably, without adversely affecting sleep compared withconventional amantadine therapy. In particular, there is a need in theart for a method of administering amantadine, or a pharmaceuticallyacceptable salt thereof, in the late afternoon or evening, e.g., after 4pm, which reduces side effects of insomnia and sleep disturbance,provides a low incidence of gastrointestinal side effects and provideseffective plasma concentrations of amantadine upon waking. In someembodiments, the extended release oral composition comprises about 68.5mg, about 137 mg, about 205.5 mg, or about 274 mg of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. Incertain embodiments, the extended release oral composition comprisesfrom about 60 mg to about 80 mg, from about 120 mg to about 155 mg, fromabout 185 mg to about 230 mg, or from about 245 mg to about 305 mg ofamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof. In some embodiments, the extended release oral compositioncomprises about 85 mg, about 170 mg, about 255 mg, or about 340 mg ofamantadine hydrochloride. In certain embodiments, the extended releaseoral composition comprises from about 75 mg to about 95 mg, from about150 mg to about 190 mg, from about 230 mg to about 285 mg, or from about305 to about 375 mg of amantadine hydrochloride.

Therefore, there exists a need in the art for improved methods ofamantadine therapy for the treatment of Parkinson's disease, LID inParkinson's Disease, and the overall symptoms of Parkinson's Disease,including motor fluctuations, which can be administered to a subjectshortly before they wish to sleep (e.g., at bedtime) without causinginsomnia or sleep disturbance and provides a low incidence ofgastrointestinal side effects. In addition, there is a need for anamantadine therapy which can be taken by the subject before they go tosleep and then provides a suitable plasma concentration of amantadinewhen they wake up, e.g., in the morning, after a full night's sleep.Furthermore, there is exists a need in the art for improved methods oftreating walking disorders in subjects with Multiple Sclerosis,including, for example, methods of improving walking speed, improvingoverall mobility, and/or improving the ability to get up.

In some aspects of the disclosure, a method of administering amantadineto a subject in need thereof is provided, said method comprising orallyadministering an extended release (ER) oral composition comprisingamantadine, or a pharmaceutically acceptable salt thereof, less thanthree hours before bedtime (e.g., the time at which the subject wishesto go to sleep). This aspect also includes the use of such compositionsand the use of amantadine, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament as described herein.Alternatively, the composition is administered less than about 4 hoursbefore bedtime. In some variations, the composition comprises less than6000 ppm organic solvent. In certain variations, the compositioncomprises less than 5500 ppm, less than 5000 ppm, less than 4500 ppm,less than 4000 ppm, less than 3500 ppm, less than 3000 ppm, less than2500 ppm, less than 2000 ppm, less than 1500 ppm, or less than 1200 ppmorganic solvent. In some variations, the composition comprises aplurality of core seeds wherein each core seed is surrounded by a drugcoating, and the plurality of coated core seeds comprises less than 6000ppm organic solvent, less than 5500 ppm, less than 5000 ppm, less than4500 ppm, less than 4000 ppm, less than 3500 ppm, less than 3000 ppm,less than 2500 ppm, less than 2000 ppm, less than 1500 ppm, or less than1200 ppm organic solvent. In some variations, the organic solvent is analcohol, such as isopropyl alcohol. In some embodiments, the organicsolvent is a linear or cyclic ketone (e.g., acetone, methyl ethylketone, etc.) In some embodiments, the organic solvent is a sulfoxide(e.g., dimethyl sulfoxide, etc.). In some embodiments, the organicsolvent is an amide (e.g., dimethyl formamide, N-methyl pyrrolidone,hexamethyl phosphorous triamide (HMPT), etc.). In some embodiments, theorganic solvent is a linear or cyclic ether (e.g., tetrahydrofuran,diethyl ether, bis(2-methoxyethyl) ether (diglyme), dimethoxy ethane(glyme), 1,4-dioxane, etc.). In some embodiments, the organic solvent isa phosphoramide (e.g., hexamethyl phosphoramide (HPMA), etc.). In someembodiments, the organic solvent is a chlorinated hydrocarbon (e.g.,chloroform, dichloromethane, dichloro ethane, carbon tetrachloride,etc.). In some embodiments, the organic solvent is a glycol (e.g.,ethylene glycol, diethylene glycol, propylene glycol, etc.). In someembodiments, the organic solvent is a, nitrogen-containing solvent(e.g., pyridine, acetonitrile, etc.). In some embodiments, the organicsolvent is an alcohol (e.g., a C₁-C₆ alcohol (e.g., ethanol, methanol,isopropanol, 1-butanol, 2-butanol, glycerol)), such as isopropylalcohol. In some embodiments, mixtures of two or more solvents can beused. In some embodiments of the levels of organic solvent describedherein, the provided level refers to the total amount of two or moreorganic solvents.

In some aspects, administration occurs less than two and a half, lessthan two, less than one and a half, less than one or less than half hourbefore bedtime.

In some aspects, the disclosure provides a method of reducing sleepdisturbance in a human subject undergoing treatment with amantadine,said method comprising administering an extended release (ER) oralcomposition comprising amantadine, or a pharmaceutically acceptable saltthereof, less than about three hours before bedtime (e.g., the time atwhich the subject wishes to go to sleep). This aspect also includes theuse of such compositions and the use of amantadine or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament as describedherein. Alternatively, the composition is administered less than about 4hours before bedtime.

In some aspects of the disclosure, amantadine, or a pharmaceuticallyacceptable salt thereof (such as the hydrochloride), in the form of acomposition described herein, is administered at a reduced amount, e.g.,68.5 to 260 mg per day, or an equivalent amount of a pharmaceuticallyacceptable salt thereof, for at least one week prior to once dailyadministration of the maintenance dose. This titration period mayimprove tolerability of the maintenance dose. In some aspects of thedisclosure, a subject is administered 68.5 or 137 mg per day ofamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof, in the form of a composition described herein, for atleast one week prior to increasing the dose to 137 or 274 mg per day, oran equivalent amount of a pharmaceutically acceptable salt thereof; inthis aspect, the amantadine may be in the form of a pharmaceuticallyacceptable salt such as amantadine hydrochloride, and the amount ofamantadine hydrochloride may be 85 or 170 mg per day for at least oneweek prior to increasing the dose to 170 or 340 mg per day. In someembodiments of methods including a titration period, and the oralpharmaceutical compositions for use in methods described herein, thesubject has Parkinson's disease. In certain embodiments, the methodcomprises treating levodopa induced dyskinesia, or fatigue, or dementia,or any other symptom of Parkinson's disease. In certain embodiments, themethod comprises decreasing OFF time, or increasing ON time withouttroublesome dyskinesia, or a combination thereof, in a subject withParkinson's disease, wherein the subject is being treated with aParkinson's medication. In some embodiments, the Parkinson's medicationis levodopa. In certain embodiments, the Parkinson's medicationcomprises levodopa. In some embodiments, the Parkinson's medicationcomprises levodopa in combination with carbidopa. In other embodimentsof methods including a titration period, and the oral pharmaceuticalcompositions for use in methods described herein, the subject hasMultiple Sclerosis. In certain embodiments, the method comprisestreating a hypokinetic disorder in a subject with Multiple Sclerosis. Insome embodiments, the hypokinetic disorder is walking impairment. Insome embodiments, treating a hypokinetic disorder comprises improvingwalking speed, improving walking ability, improving overall mobility,and/or improving the ability to get up.

In some aspects, the disclosure provides a method of treating levodopainduced dyskinesia, or fatigue, or dementia, or any other symptom ofParkinson's disease, said method comprising administering an extendedrelease (ER) oral composition comprising amantadine, or apharmaceutically acceptable salt thereof, less than about three hoursbefore bedtime (e.g., the time at which the subject wishes to go tosleep). In other aspects, the disclosure provides a method of treating ahypokinetic disorder in a subject with Multiple Sclerosis, said methodcomprising administering an extended release (ER) oral compositioncomprising amantadine, or a pharmaceutically acceptable salt thereof,less than about three hours before bedtime. Also provided herein areoral pharmaceutical compositions for use in one or more of thesemethods. For example, in some aspects, provided herein is an oralpharmaceutical composition for use in treating levodopa induceddyskinesia in a subject with Parkinson's disease, or decreasing OFF timein a subject with Parkinson's disease, or decreasing ON time withtroublesome dyskinesia in a subject with Parkinson's disease, orincreasing ON time without troublesome dyskinesia in a subject withParkinson's disease, or treating a hypokinetic disorder in subject withMultiple Sclerosis. These aspects also include the use of suchcompositions and the use of amantadine or pharmaceutically acceptablesalt thereof for the manufacture of a medicament as described herein. Insome aspects, the medicament comprises less than 6000 ppm organicsolvent. In certain variations, the composition comprises less than 5500ppm, less than 5000 ppm, less than 4500 ppm, less than 4000 ppm, lessthan 3500 ppm, less than 3000 ppm, less than 2500 ppm, less than 2000ppm, less than 1500 ppm, or less than 1200 ppm organic solvent. In somevariations, the medicament comprises a plurality of core seeds whereineach core seed is surrounded by a drug coating, and the plurality ofcoated core seeds comprises less than 6000 ppm, less than 5500 ppm, lessthan 5000 ppm, less than 4500 ppm, less than 4000 ppm, less than 3500ppm, less than 3000 ppm, less than 2500 ppm, less than 2000 ppm, lessthan 1500 ppm, or less than 1200 ppm organic solvent. In somevariations, the organic solvent is an alcohol, such as isopropylalcohol. In some embodiments, the organic solvent is a linear or cyclicketone (e.g., acetone, methyl ethyl ketone, etc.) In some embodiments,the organic solvent is a sulfoxide (e.g., dimethyl sulfoxide, etc). Insome embodiments, the organic solvent is an amide (e.g., dimethylformamide, N-methyl pyrrolidone, hexamethyl phosphorous triamide (HMPT),etc.). In some embodiments, the organic solvent is a linear or cyclicether (e.g., tetrahydrofuran, diethyl ether, bis(2-methoxyethyl) ether(diglyme), dimethoxy ethane (glyme), 1,4-dioxane, etc.). In someembodiments, the organic solvent is a phosphoramide (e.g., hexamethylphosphoramide (HPMA), etc.). In some embodiments, the organic solvent isa chlorinated hydrocarbon (e.g., chloroform, dichloromethane,dichloroethane, carbon tetrachloride, etc.). In some embodiments, theorganic solvent is a glycol (e.g., ethylene glycol, diethylene glycol,propylene glycol, etc.). In some embodiments, the organic solvent is a,nitrogen-containing solvent (e.g., pyridine, acetonitrile, etc.). Insome embodiments, the organic solvent is an alcohol (e.g., a C₁-C₆alcohol (e.g., ethanol, methanol, isopropanol, 1-butanol, 2-butanol,glycerol)), such as isopropyl alcohol. In some embodiments, mixtures oftwo or more solvents can be used. In some embodiments of the levels oforganic solvent described herein, the provided level refers to the totalamount of two or more organic solvents.

In some aspects, the disclosure provides a method of treating braininjury, brain trauma, dementia, Alzheimer's disease, stroke,Huntington's disease, ALS, Multiple Sclerosis, neurodegenerativediseases, dementias, cerebrovascular conditions, movement disorders,cranial nerve disorders, neuropsychiatric disorders, said methodcomprising administering to a subject certain extended release (ER) oralcompositions comprising amantadine, or a pharmaceutically acceptablesalt thereof, less than about three hours before bedtime (e.g., the timeat which the subject wishes to go to sleep). This aspect also includesmethods of treating symptoms associated with the aforementioneddisorders including hypokinetic disorders such as walking impairment inMultiple Sclerosis. This aspect also includes the use of suchcompositions and the use of amantadine or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament as described herein.

In some embodiments of any of the aspects herein, administration occursless than two and a half, less than two, less than one and a half, lessthan one or less than half hour before bedtime (e.g., the time at whichthe subject wishes to go to sleep).

In some embodiments of any of the aspects herein, the subject has beendiagnosed with Parkinson's disease. In some embodiments, the subject hasbeen diagnosed with Multiple Sclerosis.

In some embodiments of any of the aspects herein, the composition isadministered once nightly.

In other embodiments, the daily dose of amantadine is from 50 mg to 500mg, 60 mg to 400 mg, 60 mg to 300 mg, 137 to 274 mg (preferably 274 mg),or an equivalent amount of a pharmaceutically acceptable salt thereof.In some embodiments, the daily dose is 60 mg to 340 mg, or 170 to 340 mgof amantadine hydrochloride, or an equivalent amount of a differentpharmaceutically acceptable salt thereof, and is given in 1, 2 or 3capsules of size 0, 1 or 2, in normal and/or EL formats (e.g., sizingsystem for capsules).

In certain embodiments, the daily dose of amantadine is about 68.5 mg,about 137 mg, about 205.5 mg, or about 274 mg, or an equivalent amountof a pharmaceutically acceptable salt thereof. In certain embodiments,the daily dose of amantadine is from about 60 mg to about 80 mg, fromabout 120 mg to about 155 mg, from about 185 mg to about 230 mg, or fromabout 245 mg to about 305 mg, or an equivalent amount of apharmaceutically acceptable salt thereof. In still other embodiments,the daily dose is about 85 mg, about 170 mg, about 255 mg, or about 340mg of amantadine hydrochloride. In certain embodiments, the daily doseis from about 75 mg to about 95 mg, from about 150 mg to about 190 mg,from about 230 mg to about 285 mg, or from about 305 to about 375 mg ofamantadine hydrochloride. In any of these embodiments, the dose may, insome embodiments, be is given in 1, 2, or 3 capsules of size 0, 1 or 2,in normal and/or EL formats (e.g., sizing system for capsules).

In some embodiments of any of the aspects herein, administration of thecomposition to a subject with Parkinson's disease results in asignificant reduction in levodopa induced dyskinesia (LID). In aspecific embodiment, administration of the composition results in about20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80%reduction in levodopa induced dyskinesia. In further embodiments, thereduction in levodopa induced dyskinesia is measured on a numeric scalethat is used by the FDA to evaluate effectiveness of drugs indicated toreduce LID. In further specific embodiments, the scale used in measuringthe reduction in LID could be UDysRS, UPDRS Part IV (subscores 32, 33),MDS-UPDRS Part IV and subscores 4.1 and 4.2, Dyskinesia Rating Scale(DRS), Abnormal Involuntary Movement Scale (AIMS), or other scalesdeveloped for this purpose.

In some embodiments of any of the aspects herein, administration of theoral composition to a subject with Parkinson's disease results in asignificant reduction in Parkinson's disease symptoms, including motorfluctuations. In a specific embodiment, administration of thecomposition results in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%reduction in Parkinson's symptoms, including motor fluctuations. Infurther specific embodiments, the reduction in Parkinson's symptoms ismeasured on a numeric scale that is used by the FDA to evaluateeffectiveness of drugs indicated to reduce Parkinson's symptoms,including motor fluctuations. In further specific embodiments, the scaleused in measuring the reduction in Parkinson's symptoms, including motorfluctuations, could be the Unified Parkinson's Disease Rating Scale(UPDRS), MDS-UPDRS, or analysis of PD Diary data (for motorfluctuations).

In some embodiments of any of the aspects herein, administration of theoral composition to a subject results in a significant improvement inClinician Global Impression (CGI) or any other physician measurement ofa subject's overall condition. In a specific embodiment, administrationof the composition results in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or40% improvement in CGI. In further specific embodiments, the improvementin CGI is measured on a numeric scale that is used by the FDA toevaluate effectiveness of drugs indicated to treat CNS disorders.

In still further embodiments, provided herein is a method of, and anoral pharmaceutical composition for use in, reducing OFF time in asubject with Parkinson's disease, wherein the subject is being treatedwith a Parkinson's medication, comprising administering to the subjectan oral pharmaceutical composition as described herein. In someembodiments, the total daily amount of OFF time is reduced by at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, or at least 70%. In some embodiments, OFF time is reduced relativeto a placebo, as evaluated in a placebo-controlled double blind clinicalstudy. In other embodiments, OFF time is reduced relative to the OFFtime of the subject before beginning administering of the oralpharmaceutical composition.

In still other embodiments, provided herein is a method of, and an oralpharmaceutical composition for use in, increasing ON time withouttroublesome dyskinesia in a subject with Parkinson's disease, whereinthe subject is being treated with a Parkinson's medication, comprisingadministering to the subject a pharmaceutical composition as describedherein. In some embodiments, the total daily amount of ON time withouttroublesome dyskinesia is increased at least 10%, at least 20%, at least30%, at least 40%, at least 50%, at least 60%, or at least 70%. In someembodiments, ON time without troublesome dyskinesia is increasedrelative to a placebo, as evaluated in a placebo-controlled double blindclinical study. In other embodiments, ON time without troublesomedyskinesia is increased relative to the ON time without troublesomedyskinesia of the subject before beginning administering of the oralpharmaceutical composition.

In some embodiments of the methods of, and an oral pharmaceuticalcomposition for use in, treating a hypokinetic disorder in a subjectwith Multiple Sclerosis provided herein, walking speed is improved,walking ability is improved, overall mobility is improved, or theability to get up is improved, or any combinations thereof. In someembodiments, administration of a composition as described herein to asubject with Multiple Sclerosis results in a 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, or 60% improvement in one or more ofwalking speed, walking ability, overall mobility, or ability to get up.Overall mobility may include, for example, the total amount of walkingover the course of a day, or ability to get up at one or more times overthe course of a day, or combinations thereof. In some embodiments,walking speed, walking ability, overall mobility, or ability to get upis evaluated via at least one of the following or a combination thereof:Timed 25-Foot Walking test (T25FW), Timed Up and Go (TUG), 2 minute walktest, six minute timed walk test (6MTW), and/or, Twelve Item MultipleSclerosis Walking Scale (MSWS-12). In some embodiments, the T25FW, TUG,2 minute walk, 6MTW and/or MSWS-12 is significantly improved relative toplacebo, as evaluated in a placebo-controlled double blind clinicaltrial. In other embodiments, the T25FW, TUG, 2 minute walk, 6MTW and/orMSWS-12 is significantly improved in the subject relative to beforebeginning administration of the composition as described herein. In someembodiments, the reduction walking impairment is measured on a numericscale that is used by or accepted by the FDA or other regulatoryagencies to evaluate the effectiveness of and to approve for licensuredrugs for the treatment of walking impairment. In some embodiments,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% improvement in one or more ofthe assessment scores described herein.

In some embodiments of any of the aspects herein, there is no increasein plasma concentration of amantadine for at least one hour after theadministration at steady state plasma concentrations.

In some embodiments of any of the aspects herein, there is no increasein the plasma concentration of amantadine for at least two hours afterthe administration at steady state plasma concentrations.

In some embodiments of any of the aspects herein, the administration ofthe oral composition to a human subject at steady state amantadineplasma concentrations increases the amantadine plasma concentration byless than 5%, 10%, 15%, 20% or 25% at 1, 2, 2.5 or 3 hours followingsuch administration. For example, administration of the composition to ahuman subject at steady state amantadine plasma concentrations increasesthe amantadine plasma concentration by less than 5% at 1, 2, 2.5 or 3hours following such administration; or by less than 10% at 1, 2, 2.5 or3 hours following such administration; or by less than 15% at 1, 2, 2.5or 3 hours following such administration; or by less than 20% at 1, 2,2.5 or 3 hours following such administration; or by less than 25% at 1,2, 2.5 or 3 hours following such administration.

In some embodiments of any of the aspects herein, the amantadine has asingle dose Tmax of 11 to 19 hours. In more specific embodiments, theamantadine has a single dose Tmax of 11 to 18 hours afteradministration. In some embodiments, the Tmax for amantadine is 11, 12,13, 14 hours to 15, 16, 17, 18, 19 hours after administration to ahealthy subject of a single dose, fasting human pharmacokinetic study.

In some embodiments of any of the aspects herein, the amantadine has asteady state Tmax of 7 to 16 hours. In certain embodiments, theamantadine has a steady state Tmax of 7 to 14 hours afteradministration. In other embodiments, the amantadine has a steady stateTmax of 8 to 12 hours after administration. In some embodiments, thesteady state Tmax is the median value obtained from a multi dose,fasting human pharmacokinetic study in healthy subjects.

In some embodiments of any of the aspects described herein, at least80%, preferably at least 90%, of the amantadine or pharmaceuticallyacceptable salt thereof is released from the composition uponadministration to a subject of a single dose, fasting humanpharmacokinetic study as determined from bioavailability relative to animmediate release oral formulation of the same drug substance at asimilar dose.

In some embodiments of any of the aspects described herein, theAUC_(inf) for amantadine for the compositions of the present disclosureis 40, 41, 42, 43, 44, or 45 to 64, 66, 68, 70, or 72 ng*hr/ml per mg ofdrug of the composition as determined by administration of thecomposition to a subject of a single dose, fasting human pharmacokineticstudy. In some embodiments, compositions will have an AUC_(inf) of 42 to72 ng*hr/ml per mg of drug of the composition as determined byadministration of the composition to a subject of a single dose, fastinghuman pharmacokinetic study. In certain embodiments, compositions willhave an AUC_(inf) of 44 to 72 ng*hr/ml per mg of drug of the compositionas determined by administration of the composition to a subject of asingle dose, fasting human pharmacokinetic study.

In some embodiments described herein, the pAUC₀₋₆ for amantadine for thecompositions of the present disclosure is less than or equal to 1.0ng*hr/ml per mg of drug of the composition as determined byadministration of the composition to a subject of a single dose, fastinghuman pharmacokinetic study. Preferably the pAUC₀₋₆ for amantadine forthe composition is 0.1, 0.2, 0.3, 0.4, or 0.5 to 0.6, 0.7, 0.8, 0.9, or1.0 ng*hr/ml per mg of drug of the composition as determined byadministration of the composition to a subject of a single dose, fastinghuman pharmacokinetic study. More preferably, the pAUC₀₋₆ for amantadinefor the composition is 0.3 to 0.9 ng*hr/ml per mg of drug of thecomposition as determined by administration of the composition to asubject of a single dose, fasting human pharmacokinetic study.

In some embodiments described herein, the pAUC₀₋₈ for amantadine for thecompositions of the present disclosure is less than or equal to 2.0ng*hr/ml per mg of drug of the composition as determined byadministration of the composition to a subject of a single dose, fastinghuman pharmacokinetic study. Preferably the pAUC₀₋₈ for amantadine forthe composition is 1.0, 1.1, 1.2, 1.3, or 1.4 to 1.8, 1.9, 2.0, 2.1,2.2, 2.3, or 2.4 ng*hr/ml per mg of drug of the composition asdetermined by administration of the composition to a subject of a singledose, fasting human pharmacokinetic study. More preferably, the pAUC₀₋₈for amantadine for the composition is 1.0 to 2.0 ng*hr/ml per mg of drugof the composition as determined by administration of the composition toa subject of a single dose, fasting human pharmacokinetic study.

In some embodiments of any of the aspects herein, a once nightly oraladministration of the composition to a human subject provides a steadystate plasma concentration profile characterized by a concentrationincrease of amantadine of less than 25% at three hours after theadministration. In more specific embodiments, the steady state plasmaconcentration profile is characterized by a concentration increase ofamantadine of less than 25% at four hours after the administration.

In some embodiments of any of the aspects herein, the composition isadministered once a day and the ratio of Cmax to Cmin at steady state is1.3 to 1.8, or, more specifically, 1.4 to 1.7, or, more specifically,about 1.6.

In embodiments of any of the aspects herein, the steady state plasmaconcentration profile following multiple administrations to a humansubject of the composition at bedtime is characterized by an averageplasma concentration during the day (“C-ave-day”, defined as the averageday time amantadine plasma concentration as measured in a human PKstudy) that is 1.2 to 1.7 times the average plasma concentration duringthe night (“C-ave-night”, defined as the average night time amantadineplasma concentration as measured in a human PK study). In more specificembodiments the C-ave-day is the average amantadine plasma concentrationas measured between the hours of 5 am, 6 am, 7 am, 8 am or 9 am to thehours of 4 pm, 5 pm, 6 pm, 7 pm or 8 pm; for example, between the hoursof 6 am and 4 pm, between the hours of 6 am and 4 pm, between the hoursof 7 am and 6 pm, or between the hours of 7 am and 5 pm. The C-ave-nightis the average amantadine plasma concentration as measured between thehours of 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, 9 pm, 10 pm or 11 pm to the hoursof 5 am, 6 am, 7 am, 8 am or 9 am; for example, between the hours of 8pm and 5 am, between the hours of 10 pm and 6 am, between the hours of 7pm and 6 am, or between the hours of 8 pm and 6 am.

In some embodiments of any of the aspects herein the amantadine isadministered as a pharmaceutically acceptable salt, preferably asamantadine hydrochloride.

In some embodiments of any of the aspects herein, administration of asingle dose of the composition to a human subject provides a plasmaconcentration profile characterized by: a fractional AUC from 0 to 4hours that is less than 1%, preferably less than 0.5%, more preferablyless than 0.3%, and most preferably less than 0.2% of AUC_(0-inf); afractional AUC from 0 to 8 hours that is not more than 4.5%, preferably1.0% to 4.0%, more preferably 1.5% to 3.75%, and most preferably 1.75%to 3.5% of AUC_(0-inf); a fractional AUC from 0 to 12 hours that isabout 5% to 15%, and preferably about 7.0% to 12.0% of AUC_(0-inf); afractional AUC from 0 to 18 hours that is about 20% to 35%, andpreferably about 22.5% to 27.5% of AUC_(0-inf); and a fractional AUCfrom 0 to 24 hours that is about 34% to 48%, and preferably about 36% to44% of AUC_(0-inf). In some embodiments, the subject is a subject in asingle dose, fasted human pharmacokinetic study. In some embodiments,the single dose, fasted human pharmacokinetic study is dosed in themorning following an overnight fast.

In some embodiments of any of the aspects described herein, the oncenightly dose of amantadine in the form of a composition describedherein, may be in the range of 68.5 mg to 500 mg, or an equivalent rangeof a pharmaceutically acceptable salt thereof. Preferably, the dose ofamantadine is 50 mg to 500 mg, 60 mg to 400 mg, 60 mg to 300 mg, 137 mgto 403 mg, or an equivalent amount of a pharmaceutically acceptable saltthereof. More preferably, the dose of amantadine is 68.5 mg to 274 mg,or 137 mg to 274 mg, or an equivalent amount of a pharmaceuticallyacceptable salt thereof. Alternatively the dose of amantadinehydrochloride is 60 mg to 340 mg, or 170 mg to 340 mg. In otherembodiments, the once nightly dose of amantadine exceeds 340 mg per day,or an equivalent amount of a pharmaceutically acceptable salt thereof,e.g., the dose of amantadine is between 340 and 500 mg per day, morespecifically is between 410 and 480 mg per day, or an equivalent amountof a pharmaceutically acceptable salt thereof. In other embodiments, theonce nightly dose of a pharmaceutically acceptable salt of amantadine,for example amantadine hydrochloride, exceeds 340 mg per day, e.g., thedose of the pharmaceutically acceptable salt is between 340 and 500 mgper day, more specifically is between 410 and 480 mg per day. In variousspecific embodiments, the daily dose of amantadine may be 50 to 75 mg,70 to 95 mg, 90 to 115 mg, 110 to 135 mg, 130 to 155 mg, 150 to 175 mg,170 to 195 mg, 190 to 215 mg, 210 to 235 mg, 230 to 255 mg, 250 to 275mg, 270 to 295 mg, 290 to 305 mg, 300 to 315 mg, 310 to 325 mg, 320 to335 mg, 330 to 345 mg, 340 to 355 mg, 350 to 365 mg, 360 to 375 mg, 370to 385 mg, 380 to 395 mg, 390 to 405 mg, 400 to 415 mg, 410 to 425 mg,420 to 435 mg, 430 to 445 mg or 440 to 455 mg, or an equivalent amountof a pharmaceutically acceptable salt thereof. In still furtherembodiments, the once daily dose of amantadine is about 68.5 mg, about137 mg, about 205.5 mg, or about 274 mg or an equivalent amount of apharmaceutically acceptable salt thereof. In certain embodiments, theonce daily dose is from about 60 mg to about 80 mg, from about 120 mg toabout 155 mg, from about 185 mg to about 230 mg, or from about 245 mg toabout 305 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In some embodiments, the oncedaily dose is about 85 mg, about 170 mg, about 255 mg, or about 340 mgof amantadine hydrochloride. In certain embodiments, once daily dose isfrom about 75 mg to about 95 mg, from about 150 mg to about 190 mg, fromabout 230 mg to about 285 mg, or from about 305 to about 375 mg ofamantadine hydrochloride.

In some embodiments of any of the aspects herein, the compositioncomprises 50 mg to 500 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. More specifically, thecomposition may comprise 100 mg to 450 mg of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. Stillmore specifically, the composition may comprise 130 mg to 210 mg ofamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof. In various specific embodiments, a dosage form containingthe composition comprises 50 to 75 mg, 70 to 95 mg, 90 to 115 mg, 110 to135 mg, 130 to 155 mg, 150 to 175 mg, 170 to 195 mg, 190 to 215 mg, 210to 235 mg, 230 to 255 mg, 250 to 275 mg, 270 to 295 mg, 290 to 305 mg,300 to 315 mg, 310 to 325 mg, 320 to 335 mg, 330 to 345 mg, 340 to 355mg, or 350 to 365 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In some embodiments, the oncenightly dose of a pharmaceutically acceptable salt of amantadine is 340mg, in the form of a composition described herein. In still furtherembodiments, a dosage form of the composition comprises from about 60 mgto about 80 mg, from about 120 mg to about 155 mg, from about 185 mg toabout 230 mg, from about 245 mg to about 305 mg, about 68.5 mg, about137 mg, about 205.5 mg, or about 274 mg of amantadine, or an equivalentamount of a pharmaceutically acceptable salt thereof. In certainembodiments, a dosage form of the composition comprises from about 75 mgto about 95 mg, from about 150 mg to about 190 mg, from about 230 mg toabout 285 mg, from about 305 to about 375 mg, about 85 mg, about 170 mg,about 255 mg, or about 340 mg of amantadine hydrochloride.

In some embodiments of any of the aspects described herein, the oncenightly oral composition is administered as one, two, three or four unitdosage forms in unequally or, preferably, equally divided units. In somemore specific embodiments, the composition is administered as two orthree unit dosage forms each comprising 68.5 to 175 mg amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. Incertain embodiments, the composition is administered as two or threeunit dosage forms each comprising from about 60 mg to about 175 mg, orfrom about 60 mg to about 155 mg, or from about 60 mg to about 80 mg ofamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

In some embodiments of any of the aspects herein, the composition isadministered as two or three unit dosage forms of unequal, or preferablyequal, dosage, each comprising 68.5 to 250 mg amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. In somemore specific embodiments, the composition is administered as two unitdosage forms each comprising 150 to 180 mg amantadine, or an equivalentamount of a pharmaceutically acceptable salt thereof. In still furtherembodiments, the composition is administered as two unit dosage formseach comprising 150 to 180 mg of a pharmaceutically acceptable salt ofamantadine.

In some embodiments of any of the aspects herein, oral administration ofa single dose of the composition to a cohort of human healthy volunteersubjects in a fasted state provides an average maximum plasmaconcentration (Cmax) for amantadine of 1.1 to 2.3 ng/ml per mg ofamantadine or pharmaceutically acceptable salt thereof. In more specificembodiments, oral administration of a single dose of the composition toa cohort of human subjects in a fasted state provides an average maximumplasma concentration (Cmax) for amantadine of 1.2 to 2.0 ng/ml per mg ofamantadine or pharmaceutically acceptable salt thereof and anAUC_(0-inf) (Area under the concentration-curve curve from t=0 tot=infinity) for amantadine of 42 to 72 ng*h/mL per mg of amantadine orpharmaceutically acceptable salt thereof.

In some embodiments of any of the aspects herein, the daily oraladministration of a dose of the composition to a cohort of humansubjects provides a steady state plasma concentration profilecharacterized by at least one of: (i) a mean Cmax for amantadine of 2.2to 3.6 ng/ml per mg of amantadine or pharmaceutically acceptable saltthereof, (ii) a mean Cmin for amantadine of 1.4 to 2.0 ng/ml per mg ofamantadine or pharmaceutically acceptable salt thereof, and (iii) a meanAUC₀₋₂₄ of 46 to 72 ng*h/mL per mg of amantadine or pharmaceuticallyacceptable salt thereof. In more specific examples, all three criteriaof (i), (ii) and (iii) are met.

In more specific embodiments, the steady state plasma concentrationprofile is further characterized by: (iv) no increase in concentrationof amantadine for at least one hour after the administration; and (v)Cmax/Cmin ratio of 1.4 to 2.0. In more specific embodiments, bothcriteria of (iv) and (v) are met.

In some embodiments of any of the aspects herein the composition has anin vitro dissolution profile of amantadine or a pharmaceuticallyacceptable salt thereof which shows at least one of (i) not more than10% dissolution at 2 hours, (ii) 5% to 13% dissolution at 4 hours, (iii)20% to 43% dissolution at 6 hours, (iv) 50% to 70% dissolution at 8hours, and (v) at least 80% dissolution at 12 hours, using a USPApparatus II (Paddles) at 50 rpm with 500 ml water at 37.0±0.5° C. asthe dissolution medium. In a more specific embodiment two of criteria(i), (ii), (iii), (iv) and (v) are met. In a more specific embodiment,three of criteria (i), (ii), (iii), (iv) and (v) are met. In a morespecific embodiment, four of criteria (i), (ii), (iii), (iv) and (v) aremet. And in an even more specific embodiment, all five of criteria (i),(ii), (iii), and (iv) are met. In some embodiments, criteria (i), (iii),(iv) and (v) are met.

In some embodiments of any of the aspects herein the composition has anin vitro dissolution profile of amantadine, or a pharmaceuticallyacceptable salt thereof, which shows at least one of (i) not more than9% dissolution at 2 hours, (ii) 3% to 14% dissolution at 4 hours, (iii)20% to 43% dissolution at 6 hours, (iv) 45% to 70% dissolution at 8hours, and (v) at least 82% dissolution at 12 hours, using a USPApparatus II (Paddles) at 50 rpm with 500 ml water at 37.0±0.5° C. asthe dissolution medium. In a more specific embodiment two of criteria(i), (ii), (iii), (iv) and (v) are met. In a more specific embodiment,three of criteria (i), (ii), (iii), (iv) and (v) are met. In certainembodiments, four of criteria (i), (ii), (iii), (iv) and (v) are met.And in an even more specific embodiment, all five of criteria (i), (ii),(iii), and (iv) are met. In some embodiments, criteria (i), (iii), (iv)and (v) are met. In another aspect, the present disclosure provides anoral pharmaceutical composition comprising a plurality of coated coreseeds and a capsule shell, wherein the coated core seeds areencapsulated within the capsule shell, and wherein the coated core seedscomprise a core seed comprising an inert material; a drug coatingcomprising amantadine or a pharmaceutically acceptable salt thereof anda binder; and an extended release coating surrounding the drug coating,wherein the drug coating comprises ethyl cellulose, a pore forming agentsuch as hydroxypropyl methyl cellulose or povidone, and a plasticizer.In some embodiments of this aspect, the amantadine and binder drugcoating is prepared and applied to the core seed without the use oforganic solvents.

In another aspect, the present disclosure provides an oralpharmaceutical composition for use in the methods of the aspectsdescribed herein, wherein said composition is for oral administrationand comprises a capsule for oral administration, said capsule comprisinga plurality of coated core seeds comprising: (a) a core seed, (b) a drugcoating surrounding the core seed, wherein the drug coating comprisesamantadine, or a pharmaceutically acceptable salt thereof, and (c) anextended release coating surrounding the drug coating. In someembodiments of this aspect, the drug coating comprises amantadine or apharmaceutically acceptable salt thereof and one or more binders, andthe drug coating is prepared and applied to the core seed without theuse of organic solvents.

In some embodiments, the extended release coating comprises ethylcellulose and at least one of povidone and hydroxypropyl methylcellulose, and a plasticizer. In a more specific embodiment, theextended release coating comprises ethyl cellulose, povidone, and aplasticizer.

In some embodiments, the drug coating comprises amantadine and a binder,and surrounds the core seed. In some embodiments, the core seed is asugar sphere (nonpareil) or microcrystalline cellulose seed (e.g.Celphere®). In a more specific embodiment, the core seed is amicrocrystalline cellulose core. In another specific embodiment, thecore seed has a diameter in the range of 100 microns to 1,000 microns.In additional specific embodiments, the core seed has a diameter of 100,200, 300, 400, 500, 600 or 700 microns. In additional specificembodiments, 90% or more of the core seeds of the composition have adiameter of 100 to 200 microns, 150 to 250 microns, 200 to 300 microns,250 to 350 microns, 300 to 400 microns, 350 to 450 microns, 400 to 500microns, 500 to 600 microns, 550 to 650 microns, 600 to 700 microns. Insome embodiments, the core seed has a diameter of less than 500 microns.

In some embodiments, based on the combined weight of the core seed, thedrug coating, and the extended release coating, the amantadine, or apharmaceutically acceptable salt thereof, is present in amounts from 20to 80 wt %, with a bulk density of 0.3 to 1.2 g/cm³.

In some embodiments, based on the combined weight of the core seed, thedrug coating, and the extended release coating, the amantadine, or apharmaceutically acceptable salt thereof, is present in amounts from 40to 60 wt %, with a bulk density of 0.5 to 1.2 g/cm³.

In some embodiments, based on the combined weight of the core seed, thedrug coating, and the extended release coating, the amantadine, or apharmaceutically acceptable salt thereof, is present in amounts from 60to 80 wt %, with a bulk density of 0.5 to 1.2 g/cm³.

In some embodiments, based on the combined weight of the core seed, thedrug coating, and the extended release coating, the binder is present inamounts from 8 to 25 wt %,

In some embodiments, based on the combined weight of the core seed, thedrug coating, and the extended release coating, the core seed is presentin amounts from 8 to 25 wt %,

In some embodiments, based on the combined weight of the core seed, thedrug coating, and the extended release coating, the ethyl cellulose ispresent in amounts from 10 to 24 wt %,

In some embodiments, based on the combined weight of the core seed, thedrug coating, and the extended release coating, the povidone is presentin amounts from 1 to 4 wt %,

In some embodiments, based on the combined weight of the core seed, thedrug coating, and the extended release coating, the plasticizer ispresent in amounts from 1 to 4 wt %.

In some embodiments, the coated core seeds have an average diameter inthe range of 200 microns to 1700 microns. In additional specificembodiments, the coated core seeds have an average diameter of 200, 300,400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300 or 1500 microns. Inadditional embodiments, the coated core seeds have an average diameterranging from 200, 300, 400, 500, 600, 700, 800, 900 microns to 400, 500,600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 microns. Incertain specific embodiments, the coated core seeds have an averagediameter of less than 1000 microns, e.g., from 500 to 1000 microns.

In some embodiments, the coated core seeds further comprise a sealcoating surrounding the drug coating, wherein the extended releasecoating surrounds the seal coating. In some embodiments, an inertcoating can be applied to the inert core seed prior to drug coating oron drug-coated core seeds or on extended release coated core seeds. Inanother embodiment, an enteric coating can be applied to the drug coatedcore seeds or extended release coated core seeds.

In some embodiments, the drug coating comprises a binder, selected fromthe group consisting of hydroxypropyl methyl cellulose, copovidone, andmixtures thereof.

In some embodiments, the composition described herein is provided in asize 3, size 2, size 1, size 0 or size 00 capsules in normal and/or ELformats.

In some embodiments, the therapeutically effective daily dose of thecomposition described herein is administered in no more than twocapsules. In another embodiment, the therapeutically effective dailydose of the composition is administered in no more than three size 1capsules. In another embodiment, the therapeutically effective dailydose of the composition is administered in no more than two size 0capsules. In yet other embodiments, the therapeutically effective dailydose of the composition is administered in no more than two size 1capsules. In another embodiment, the therapeutically effective dailydose of the composition is administered in no more than three size 2capsules.

In some embodiments, the composition described herein is provided in anamount of 50 to 110 mg of amantadine or an equivalent amount of apharmaceutically acceptable salt thereof in a size 2 capsule, and in theamount of 110 mg to 210 mg of amantadine or an equivalent amount of apharmaceutically acceptable salt thereof in a size 1 capsule. Inadditional embodiments, the composition described herein comprisescoated core seeds of diameter 300 to 1000 microns, with amantadine orpharmaceutically acceptable salt thereof content of 40-80% wt % and at abulk density of 0.5-1.2 g/cm³. In certain embodiments, the compositiondescribed herein has an in vitro dissolution profile of amantadine whichshows at least one of (i) not more than 10% dissolution in 2 hours, (ii)5% to 13% dissolution in 4 hours, (iii) 20% to 43% dissolution at 6hours, (iv) 45% to 70% dissolution in 8 hours, and (v) at not less than82% dissolution in 12 hours, using a USP Apparatus II (Paddles) at 50rpm with 500 ml water at 37.0±0.5° C. as the dissolution medium. In amore specific embodiment two of criteria (i), (ii), (iii), (iv) and (v)are met. In some embodiments, three of criteria (i), (ii), (iii), (iv)and (v) are met. In a more specific embodiment, four of criteria (i),(ii), (iii), (iv) and (v) are met. In an even more specific embodiment,all five of criteria (i), (ii), (iii), (iv) and (v) are met. In certainembodiments, criteria (i), (iii), (iv) and (v) are met.

In some embodiments, the plasticizer is selected from the groupconsisting of medium chain triglycerides, diethyl phthalate, citrateesters, polyethylene glycol, glycerol, acetylated glycerides, and castoroil. In certain embodiments, the plasticizer is medium chaintriglycerides, e.g. Miglyol 812 N.

In other embodiments, the present disclosure provides method of treatingParkinson's disease and/or LID in a human subject in need thereof, saidmethod comprising orally administering a composition of any of theaspects herein. In certain embodiments, the present disclosure providesa method of treating disease in a human subject in need thereof, saidmethod comprising orally administering a composition of any of theaspects herein once nightly at nighttime, administering 1, 2 or 3 dosageforms.

References to administering amantadine or a pharmaceutically acceptablesalt thereof to a subject in need thereof include treating a subjectwith a disease or condition, including an iatrogenic condition (e.g.,LID), which may be treated, prevented or cured by a NMDA antagonist.More specifically, administering amantadine or a pharmaceuticallyacceptable salt thereof to a subject in need thereof includes treating asubject diagnosed with Parkinson's Disease, brain injury, brain trauma,dementia, Alzheimer's disease, stroke, Huntington's disease, ALS,Multiple Sclerosis, neurodegenerative diseases, dementias,cerebrovascular conditions, movement disorders, cranial nerve disorders,neuropsychiatric disorders and other CNS disorders.

Some embodiments described herein provide a method of improving CGI in asubject with Parkinson's disease, comprising administering to saidsubject once nightly, 0 to 4 hours before bedtime a compositioncomprising 260 to 420 mg amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof, and at least one releasemodifying excipient. In some embodiments, the composition comprises 260to 340 mg amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprises260 mg amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprises340 mg of a pharmaceutically acceptable salt of amantadine. In someembodiments, the change in CGI is determined in a placebo controlled,double blind clinical study. Also provided is an oral pharmaceuticalcomposition as described herein for use in improving CGI in a subjectwith Parkinson's disease, comprising administering to said subject oncenightly, 0 to 4 hours before bedtime.

Some embodiments described herein provide a method resulting in at leastone, preferably at least two, of the results selected from the groupconsisting of (A) increasing ON time without troublesome dyskinesia; and(B) reducing OFF time; and (C) improving CGI; in a subject with a CNSdisorder, comprising administering to said subject once nightly, 0 to 4hours before bedtime a composition comprising 260 to 420 mg amantadine,or an equivalent amount of a pharmaceutically acceptable salt thereof,and at least one release modifying excipient. In some embodiments, thecomposition comprises 260 to 340 mg amantadine, or an equivalent amountof a pharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises 260 mg amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises 340 mg of a pharmaceutically acceptable salt ofamantadine. In some embodiments, the change in ON time withoutdyskinesia, the OFF time and/or the CGI are determined in a placebocontrolled, double blind clinical study using the PD Home diary. In someembodiments, the CGI is determined by a question completed by theinvestigator. Also provided is an oral pharmaceutical composition asdescribed herein for use in at least one, or at least two, of theresults selected from the group consisting of (A) increasing ON timewithout troublesome dyskinesia; (B) reducing OFF time; and (C) improvingCGI; in a subject with a CNS disorder, comprising administering to saidsubject once nightly, 0 to 4 hours before bedtime.

Some embodiments described herein provide a method resulting in at leastone, preferably at least two, of the results selected from the groupconsisting of (A) increasing ON time without troublesome dyskinesia; and(B) reducing OFF time; and (C) improving CGI; in a subject with a CNSdisorder, comprising administering to said subject once daily, acomposition comprising 260 to 420 mg amantadine, or an equivalent amountof a pharmaceutically acceptable salt thereof, and at least one releasemodifying excipient. Also provided herein is an oral pharmaceuticalcomposition for use in such methods. In some embodiments, thecomposition comprises 260 to 340 mg amantadine, or an equivalent amountof a pharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises 260 mg amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises 340 mg of a pharmaceutically acceptable salt ofamantadine. In some embodiments, the change in ON time withoutdyskinesia, the OFF time and/or the CGI are determined in a placebocontrolled, double blind clinical study using the PD Home diary. In someembodiments, the CGI is determined by a question completed by theinvestigator. In some such methods, the C-ave-day is 1.2 to 1.7 timesthe C-ave-night; in some embodiments of the method, the C-ave-day isdetermined between the hours of 8 am to 8 pm and the C-ave-night isdetermined between the hours of 8 pm to 8 am. In certain embodiments ofthe method, C-ave-day is determined between the hours of 5 am to 4 pmand C-ave-night is determined between the hours of 8 pm to 5 am. In somesuch methods, administration of a single dose of the composition to acohort of human healthy volunteer subjects in a fasted state provides anaverage maximum plasma concentration (Cmax) of 1.1 to 2.0 ng/ml per mgof amantadine, or a pharmaceutically acceptable salt thereof, or anAUC_(0-inf) (Area under the concentration-curve curve from t=0 tot=infinity) of 44 to 72 ng*h/mL per mg of amantadine, or apharmaceutically acceptable salt thereof, or both. In some such methods,the daily oral administration of a dose of the composition to a cohortof human subjects provides a steady state plasma concentration profilecharacterized by at least one of: (i) a mean Cmax of 2.4 to 3.1 ng/mlper mg of amantadine, or a pharmaceutically acceptable salt thereof,(ii) a mean Cmin of 1.4 to 2.1 ng/ml per mg of amantadine, or apharmaceutically acceptable salt thereof, and (iii) a mean AUC₀₋₂₄ of 44to 72 ng*h/mL per mg of amantadine, or a pharmaceutically acceptablesalt thereof, in more specific methods, all three criteria of (i), (ii)and (iii) are met.

The PD home diary is described in Hauser, et al., “A Home Diary toAssess Functional Status in Patients with Parkinson's Disease with MotorFluctuations and Dyskinesia”, Clin. Neuropharmacol., 23(3), pp. 75-81(2000), which is incorporated herein by reference in its entirety. Asused herein, the terms “ON time” and “OFF time,” have the meaningsdescribed by Hauser et al. Id. Briefly, ON time is the period duringwhich Parkinson's medication is providing benefit with regard tomobility, slowness, and stiffness; and OFF time is the period duringwhich Parkinson's medication has worn off and is no longer providingbenefit with regard to mobility, slowness, and stiffness. Id. Thesemeasures of time are separate from the scales used to measure reductionin LID, which primarily assess the change in dyskinesia severity orintensity. As such, these scales capture the benefit throughout the dayand night of a given treatment for all four motor states. In someembodiments, a product profile includes benefits across this measure.

Dyskinesia is involuntary twisting, turning movements. Id. Thesemovements are an effect of medication (i.e., levodopa) and occur duringON time. Id. Dyskinesia is distinct from tremor, which is shaking backand forth, a symptom of the underlying Parkinson's disease. Troublesomedyskinesia is dyskinesia that causes at least some difficulty withfunction. Id.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution profiles for two formulations described inExamples 1 and 2.

FIG. 2 and FIG. 3 show the mean concentrations over time afteradministration of two formulations of Examples 1 and 2 in the singledose fasting human pharmacokinetic study described in Example 4.

FIG. 4 is a schematic showing the isopropanol content at various pointsduring drug-coating of pellets, without intermediate drying (Batch 166).

FIG. 5 is a schematic showing the isopropanol content at various pointsduring drug-coating of pellets, using intermediate drying steps (Batch167).

FIG. 6 is a graph demonstrating the effect of intermediate drying on theisopropanol content of drug-coated pellets.

FIG. 7 is a graph demonstrating the effect of different dryingconditions on the isopropanol content of drug-coated pellets.

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutical compositions formulated for oral administration mayinclude, for example, tablets, capsules, or a plurality of pelletswithin a capsule. These formulations may include one or more coatings,such as a drug coating in the case of compositions with pellets. In thepreparation of pharmaceutical compositions, it is common to dissolve ordisperse one or more ingredients (such as the active drug) in a solvent(such as an organic solvent) to make a mixture; use the mixture in oneor more steps of the process; and then remove at least a portion of thesolvent to produce the intended product. In the preparation of solidformulations, for example, pellets within a capsule, all or nearly allof the solvent is removed, such as by the application of heat and/orflowing of a gas. Thus, some pharmaceutical formulations have a verylow, if any, residual solvent content.

As described herein, administration of compositions amantadine or apharmaceutically acceptable salt thereof, for example in the treatmentof symptoms of Parkinson's disease, can cause gastrointestinal sideeffects such as dry mouth, loss of appetite, nausea, vomiting, ordiarrhea. The inventors have surprisingly found that in preparingcertain formulations of oral compositions comprising amantadine, or apharmaceutically acceptable salt thereof, the use of an organic solventin certain steps results in residual organic solvent content in thefinal pharmaceutical composition, and that additional efforts to removesaid organic solvent (such as increased drying time) did not lead toconsistently lowered organic solvent content. However, by replacing theorganic solvent in certain steps with water (though not necessarily allsteps), compositions with lower residual organic solvent content couldbe obtained. Thus, in some embodiments, organic solvent is still used inone or more steps, but the resulting final formulation has a lowresidual organic solvent content. In some embodiments, the amount oforganic solvent is reduced in one or more steps, for example, byreplacing a portion of the organic solvent with water, and the resultingfinal formulation has a low residual organic solvent content. Theinventors further surprisingly found that a higher incidence ofgastrointestinal side effects was associated with administration of thecompositions with higher residual organic solvent content. Thus,provided herein are oral pharmaceutical compositions comprisingamantadine, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient, with low organic solvent content.Also provided herein are methods of administering oral pharmaceuticalcompositions comprising amantadine or a pharmaceutically acceptable saltthereof.

I. Methods of Administration

The disclosure provides a method of orally administering once daily acomposition comprising a therapeutically effective dose of amantadine,or a pharmaceutically acceptable salt thereof with a reduced incidenceof gastrointestinal adverse events as compared to known amantadineformulations. Some embodiments described herein provide a method ofincreasing the ON time without dyskinesia in a subject with Parkinson'sdisease, comprising orally administering to the subject once per day, 0to 4 hours before bedtime, a composition comprising 260 to 420 mgamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof (e.g., amantadine hydrochloride) and at least one releasemodifying excipient. In certain embodiments, provided is a method ofincreasing the ON time without dyskinesia in a subject with Parkinson'sdisease, comprising orally administering to the subject once per day, 0to 4 hours before bedtime, a composition comprising about 68.5 mg, about137 mg, about 205.5 mg, about 274 mg, from about 60 mg to about 80 mg,from about 120 mg to about 155 mg, from about 185 mg to about 230 mg, orfrom about 245 mg to about 305 mg of amantadine, or an equivalent amountof a pharmaceutically acceptable salt thereof (e.g., amantadinehydrochloride), and at least one release modifying excipient. In someembodiments, the oral composition is administered at night. In some suchmethods, the change in ON time without dyskinesia is determined in aplacebo controlled, double blind clinical study using the PD Home Diary.In some such methods, the amantadine is provided as amantadinehydrochloride and the dose is from 300 to 360 mg per day, particularly330 to 350 mg per day, and in particular 340 mg per day. In someembodiments, the once daily dose also provides a treatment that reducesor results in no increase in sleep related adverse events as compared toplacebo (as determined from a randomized, double blind, placebocontrolled study in subjects with Parkinson's).

Some embodiments described herein provide a method of reducing the ONtime with dyskinesia in a subject with Parkinson's disease comprisingorally administering to said subject once per day, 0 to 4 hours beforebedtime a composition comprising 260 to 420 mg amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof (e.g.,amantadine hydrochloride), and at least one release modifying excipient.In certain embodiments described herein, provided is a method ofreducing the ON time with dyskinesia in a subject with Parkinson'sdisease comprising orally administering to said subject once per day, 0to 4 hours before bedtime a composition comprising about 68.5 mg, about137 mg, about 205.5 mg, about 274 mg, from about 60 mg to about 80 mg,from about 120 mg to about 155 mg, from about 185 mg to about 230 mg, orfrom about 245 mg to about 305 mg of amantadine, or an equivalent amountof a pharmaceutically acceptable salt thereof (e.g., amantadinehydrochloride), and at least one release modifying excipient. In someembodiments, the oral composition is administered once nightly. In somesuch methods, the change in ON time with dyskinesia is determined in aplacebo controlled, double blind clinical study using the PD Home Diary.In some such methods, the dose of a pharmaceutically acceptable salt ofamantadine, is from 300 to 360 mg per day, particularly 330 to 350 mgper day, and in particular 340 mg per day.

Some embodiments described herein provide a method of reducing the ONtime with troublesome dyskinesia in a subject with Parkinson's disease,comprising orally administering to said subject once per day, 0 to 4hours before bedtime, a composition comprising 260 to 420 mg amantadine,or an equivalent amount of a pharmaceutically acceptable salt thereof(e.g., amantadine hydrochloride), and at least one release modifyingexcipient. In certain embodiments described herein, provided is a methodof reducing the ON time with troublesome dyskinesia in a subject withParkinson's disease, comprising orally administering to said subjectonce per day, 0 to 4 hours before bedtime, a composition comprisingabout 68.5 mg, about 137 mg, about 205.5 mg, about 274 mg, from about 60mg to about 80 mg, from about 120 mg to about 155 mg, from about 185 mgto about 230 mg, or from about 245 mg to about 305 mg of amantadine, oran equivalent amount of a pharmaceutically acceptable salt thereof(e.g., amantadine hydrochloride), and at least one release modifyingexcipient. In some such methods, the change in ON time withouttroublesome dyskinesia is determined in a placebo controlled, doubleblind clinical study using the PD Home Diary. In some embodiments, thecomposition comprises 260 to 340 mg amantadine hydrochloride. In somesuch methods, the dose comprises amantadine hydrochloride from 300 to360 mg per day, particularly 330 to 350 mg per day, and in particular340 mg per day. In some embodiments, the oral composition isadministered at night.

Some embodiments described herein provide a method of reducing the OFFtime in a subject with Parkinson's disease comprising orallyadministering to said subject once per day, 0 to 4 hours before bedtime,a composition comprising 260 to 340 mg amantadine hydrochloride and atleast one release modifying excipient. In certain embodiments describedherein, provided is a method of reducing the OFF time in a subject withParkinson's disease comprising orally administering to said subject onceper day, 0 to 4 hours before bedtime, a composition comprising about68.5 mg, about 137 mg, about 205.5 mg, about 274 mg, from about 60 mg toabout 80 mg, from about 120 mg to about 155 mg, from about 185 mg toabout 230 mg, or from about 245 mg to about 305 mg of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof (e.g.,amantadine hydrochloride), and at least one release modifying excipient.In some such methods, the change in OFF time is determined in a placebocontrolled, double blind clinical study using the PD Home Diary. In somesuch methods, the dose of amantadine hydrochloride is from 300 to 360 mgper day, particularly 330 to 350 mg per day, and in particular 340 mgper day. In some embodiments, the composition is administered at night.

In some embodiments, provided herein is a method of reducing OFF time ina subject with Parkinson's disease, wherein the subject is being treatedwith a Parkinson's medication, comprising administering to the subjectan oral pharmaceutical composition as described herein. Also providedherein is an oral pharmaceutical composition for use in reducing OFFtime in a subject with Parkinson's disease, wherein the subject is beingtreated with a Parkinson's medication. In some embodiments, theParkinson's medication is levodopa. In some embodiments, the Parkinson'smedication comprises levodopa. For example, in some embodiments, theParkinson's medication comprises levodopa in combination withcarboidopa. In certain embodiments, the Parkinson's medication compriseslevodopa in combination with carbidopa and entacapone. In someembodiments, the oral pharmaceutical composition is administered to thesubject once per day, 0 to 4 hours before bedtime. In some embodiments,the oral pharmaceutical composition is administered to the subject onceper day, 0 to 3 hours before bedtime. In some embodiments of the methodand oral pharmaceutical composition for use as provided herein, the oralpharmaceutical composition comprises 50 mg to 500 mg of amantadine or anequivalent amount of a pharmaceutically acceptable salt thereof, and atleast one release modifying excipient. In some embodiments, the oralpharmaceutical composition comprises between 100 mg to 450 mg, or 120 to150 mg, or 260 mg to 305 mg, or 137 mg, or 174 mg of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral pharmaceutical composition comprises between 245mg to 305 mg amantadine. In some embodiments, the oral pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of amantadinein an amount equivalent to between 245 mg to 305 mg amantadine. In otherembodiments, the oral pharmaceutical composition comprises between 120mg to 150 mg amantadine. In some embodiments, the oral pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of amantadinein an amount equivalent to between 120 mg to 150 mg amantadine. Incertain embodiments, the pharmaceutically acceptable salt is amantadinehydrochloride. In some embodiments, the extended release oralcomposition comprises about 68.5 mg, about 137 mg, about 205.5 mg, about274 mg of amantadine, from about 60 mg to about 80 mg, from about 120 mgto about 155 mg, from about 185 mg to about 230 mg, or from about 245 mgto about 305 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In some embodiments, theextended release oral composition comprises about 85 mg, about 170 mg,about 255 mg, about 340 mg from about 75 mg to about 95 mg, from about150 mg to about 190 mg, from about 230 mg to about 285 mg, or from about305 to about 375 mg of amantadine hydrochloride.

In some embodiments, the total daily amount of OFF time is reduced by atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, or at least 70%. In some embodiments, the total daily amountof OFF time is reduced by between 10% to 70%, between 10% to 60%,between 10% to 50%, between 10% to 40%, between 10% to 30%, between 10%to 20%, between 20% to 70%, between 20% to 60%, between 20% to 50%,between 20% to 40%, between 20% to 30%, between 30% to 70%, between 30%to 60%, between 30% to 50%, or between 30% to 40%. In some embodiments,the total daily amount of OFF time is reduced by at least 0.25 hours,0.5 hours, by at least 0.75 hours, by at least 1.0 hours, by at least1.25 hours, or by at least 1.5 hours.

In certain embodiments, the total daily amount of OFF time is reduced inan amount as described herein after at least 6 weeks of administeringonce daily to the subject the oral pharmaceutical composition, after atleast 7 weeks of administering once daily to the subject the oralpharmaceutical composition, after at least 8 weeks of administering oncedaily to the subject the oral pharmaceutical composition, after at least9 weeks of administering once daily to the subject the oralpharmaceutical composition, after at least 10 weeks of administeringonce daily to the subject the oral pharmaceutical composition, after atleast 11 weeks of administering once daily to the subject the oralpharmaceutical composition, or after at least 12 weeks of administeringonce daily to the subject the oral pharmaceutical composition. Incertain embodiments, wherein the subject is first administered a firstcomposition comprising lower dose of amantadine or an equivalent amountof a pharmaceutically acceptable salt thereof during a lead-in,titration period, the total daily amount of OFF time is reduced in anamount as described herein after at least 6 weeks of administering oncedaily to the subject a second oral pharmaceutical composition, after atleast 7 weeks of administering once daily to the subject a second oralpharmaceutical composition, after at least 8 weeks of administering oncedaily to the subject a second oral pharmaceutical composition, after atleast 9 weeks of administering once daily to the subject a second oralpharmaceutical composition, after at least 10 weeks of administeringonce daily to the subject a second oral pharmaceutical composition,after at least 11 weeks of administering once daily to the subject asecond oral pharmaceutical composition, or after at least 12 weeks ofadministering once daily to the subject a second oral pharmaceuticalcomposition, wherein the second oral pharmaceutical composition has ahigher dose of amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, OFF time is reducedrelative to a placebo, as evaluated in a placebo-controlled clinicalstudy. In other embodiments, OFF time is reduced relative to the OFFtime of the subject before beginning administering of the oralpharmaceutical composition. In certain embodiments, OFF time is reducedrelative to the OFF time of the subject before beginning administeringof the first oral pharmaceutical composition, wherein the subject isadministered a first oral pharmaceutical composition during a lead-intitration period (with a lower dose of amantadine or an equivalentamount of a pharmaceutically acceptable salt thereof) and then a secondoral pharmaceutical composition (with a higher dose of amantadine or anequivalent amount of a pharmaceutically acceptable salt thereof).

In some embodiments, provided herein is a method of increasing ON timewithout troublesome dyskinesia in a subject with Parkinson's disease,wherein the subject is being treated with a Parkinson's medication,comprising administering to the subject an oral pharmaceuticalcomposition as described herein. Also provided herein is an oralpharmaceutical composition for use in increasing ON time withouttroublesome dyskinesia in a subject with Parkinson's disease, whereinthe subject is being treated with a Parkinson's medication. In someembodiments, the Parkinson's medication is levodopa. In someembodiments, the Parkinson's medication comprises levodopa. For example,in some embodiments, the Parkinson's medication comprises levodopa incombination with carboidopa. In certain embodiments, the Parkinson'smedication comprises levodopa in combination with carbidopa andentacapone. In some embodiments, the oral pharmaceutical composition isadministered to the subject once per day, 0 to 4 hours before bedtime.In some embodiments, the oral pharmaceutical composition is administeredto the subject once per day, 0 to 3 hours before bedtime. In someembodiments of the method and oral pharmaceutical composition for use asprovided herein, the oral pharmaceutical composition comprises 50 mg to500 mg of amantadine or an equivalent amount of a pharmaceuticallyacceptable salt thereof, and at least one release modifying excipient.In some embodiments, the oral pharmaceutical composition comprisesbetween 100 mg to 450 mg, or 120 to 150 mg, or 260 mg to 305 mg, or 137mg, or 174 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In some embodiments, the oralpharmaceutical composition comprises between 245 mg to 305 mgamantadine. In some embodiments, the oral pharmaceutical compositioncomprises a pharmaceutically acceptable salt of amantadine in an amountequivalent to between 245 mg to 305 mg amantadine. In other embodiments,the oral pharmaceutical composition comprises between 120 mg to 150 mgamantadine. In some embodiments, the oral pharmaceutical compositioncomprises a pharmaceutically acceptable salt of amantadine in an amountequivalent to between 120 mg to 150 mg amantadine. In certainembodiments, the pharmaceutically acceptable salt is amantadinehydrochloride. In some embodiments, the extended release oralcomposition comprises about 68.5 mg, about 137 mg, about 205.5 mg, about274 mg of amantadine, from about 60 mg to about 80 mg, from about 120 mgto about 155 mg, from about 185 mg to about 230 mg, or from about 245 mgto about 305 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In some embodiments, theextended release oral composition comprises about 85 mg, about 170 mg,about 255 mg, about 340 mg from about 75 mg to about 95 mg, from about150 mg to about 190 mg, from about 230 mg to about 285 mg, or from about305 to about 375 mg of amantadine hydrochloride.

In some embodiments, the total daily amount of ON time withouttroublesome dyskinesia is increased by at least 10%, at least 20%, atleast 30%, at least 40%, at least 50%, at least 60%, or at least 70%. Insome embodiments, the total daily amount of ON time without troublesomedyskinesia is increased by between 10% to 70%, between 10% to 60%,between 10% to 50%, between 10% to 40%, between 10% to 30%, between 10%to 20%, between 20% to 70%, between 20% to 60%, between 20% to 50%,between 20% to 40%, between 20% to 30%, between 30% to 70%, between 30%to 60%, between 30% to 50%, or between 30% to 40%. In some embodiments,the total daily amount of ON time without troublesome dyskinesia isincreased by at least 0.25 hours, 0.5 hours, by at least 0.75 hours, byat least 1.0 hours, by at least 1.25 hours, or by at least 1.5 hours.

In certain embodiments, the total daily amount of ON time withouttroublesome dyskinesia is increased in an amount as described hereinafter at least 6 weeks of administering once daily to the subject theoral pharmaceutical composition, after at least 7 weeks of administeringonce daily to the subject the oral pharmaceutical composition, after atleast 8 weeks of administering once daily to the subject the oralpharmaceutical composition, after at least 9 weeks of administering oncedaily to the subject the oral pharmaceutical composition, after at least10 weeks of administering once daily to the subject the oralpharmaceutical composition, after at least 11 weeks of administeringonce daily to the subject the oral pharmaceutical composition, or afterat least 12 weeks of administering once daily to the subject the oralpharmaceutical composition. In certain embodiments, wherein the subjectis first administered a first composition comprising lower dose ofamantadine or an equivalent amount of a pharmaceutically acceptable saltthereof during a lead-in, titration period, the total daily amount of ONtime without troublesome dyskinesia is increased in an amount asdescribed herein after at least 6 weeks of administering once daily tothe subject a second oral pharmaceutical composition, after at least 7weeks of administering once daily to the subject a second oralpharmaceutical composition, after at least 8 weeks of administering oncedaily to the subject a second oral pharmaceutical composition, after atleast 9 weeks of administering once daily to the subject a second oralpharmaceutical composition, after at least 10 weeks of administeringonce daily to the subject a second oral pharmaceutical composition,after at least 11 weeks of administering once daily to the subject asecond oral pharmaceutical composition, or after at least 12 weeks ofadministering once daily to the subject a second oral pharmaceuticalcomposition, wherein the second oral pharmaceutical composition has ahigher dose of amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, ON time withouttroublesome dyskinesia is increased relative to a placebo, as evaluatedin a placebo-controlled clinical study. In other embodiments, ON timewithout troublesome dyskinesia is increased relative to the ON timewithout troublesome dyskinesia in the subject before beginningadministering of the oral pharmaceutical composition. In certainembodiments, ON time without troublesome dyskinesia is increasedrelative to the ON time without troublesome dyskinesia of the subjectbefore beginning administering of the first oral pharmaceuticalcomposition, wherein the subject is administered a first oralpharmaceutical composition during a lead-in titration period (with alower dose of amantadine or an equivalent amount of a pharmaceuticallyacceptable salt thereof) and then a second oral pharmaceuticalcomposition (with a higher dose of amantadine or an equivalent amount ofa pharmaceutically acceptable salt thereof).

In still further embodiments, provided herein is a method of treating ahypokinetic disorder in a subject with Multiple Sclerosis, comprisingadministering to the subject an oral pharmaceutical composition asdescribed herein. Also provided herein is an oral pharmaceuticalcomposition for use in treating a hypokinetic disorder in a subject withMultiple Sclerosis. In some embodiments, the oral pharmaceuticalcomposition is administered to the subject once per day, 0 to 4 hoursbefore bedtime. In some embodiments, the oral pharmaceutical compositionis administered to the subject once per day, 0 to 3 hours beforebedtime. In some embodiments of the method and oral pharmaceuticalcomposition for use as provided herein, the oral pharmaceuticalcomposition comprises 50 mg to 500 mg of amantadine or an equivalentamount of a pharmaceutically acceptable salt thereof, and at least onerelease modifying excipient. In some embodiments, the oralpharmaceutical composition comprises between 100 mg to 450 mg, or 120 to150 mg, or 260 mg to 305 mg, or 137 mg, or 174 mg of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. In someembodiments, the oral pharmaceutical composition comprises between 245mg to 305 mg amantadine. In some embodiments, the oral pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of amantadinein an amount equivalent to between 245 mg to 305 mg amantadine. In otherembodiments, the oral pharmaceutical composition comprises between 120mg to 150 mg amantadine. In some embodiments, the oral pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of amantadinein an amount equivalent to between 120 mg to 150 mg amantadine. Incertain embodiments, the pharmaceutically acceptable salt is amantadinehydrochloride. In some embodiments, the extended release oralcomposition comprises about 68.5 mg, about 137 mg, about 205.5 mg, about274 mg of amantadine, from about 60 mg to about 80 mg, from about 120 mgto about 155 mg, from about 185 mg to about 230 mg, or from about 245 mgto about 305 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In some embodiments, theextended release oral composition comprises about 85 mg, about 170 mg,about 255 mg, about 340 mg from about 75 mg to about 95 mg, from about150 mg to about 190 mg, from about 230 mg to about 285 mg, or from about305 to about 375 mg of amantadine hydrochloride.

In certain embodiments of the methods for, and oral pharmaceuticalcompositions for use in, treating a hypokinetic disorder in a subjectwith Multiple Sclerosis, walking speed is improved, walking ability isimproved, overall mobility is improved, or the ability to get up isimproved, after beginning administration of the oral pharmaceuticalcomposition. In certain embodiments, a two or more, or three or more, oreach of walking speed is improved, walking ability is improved, overallmobility is improved, or the ability to get up is improved, afterbeginning administration of the oral pharmaceutical composition. In someembodiments, administration of a composition as described herein to asubject with Multiple Sclerosis results in a 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, or 60% improvement in one or more ofwalking speed, walking ability, overall mobility, or ability to get up.In certain embodiments, administration of a composition as describedherein to a subject with Multiple Sclerosis results in between 10% to60%, between 10% to 50%, between 10% to 40%, between 10% to 30%, between10% to 20%, between 20% to 60%, between 20% to 50%, between 20% to 40%,between 20% to 30%, between 30% to 60%, between 30% to 50%, or between30% to 40% improvement in one or more of walking speed, walking ability,overall mobility, or ability to get up. Overall mobility may include,for example, the total amount of walking over the course of a day, orability to get up at one or more times over the course of a day, orcombinations thereof. In some embodiments, walking speed, walkingability, overall mobility, or ability to get up is evaluated via atleast one of the following or a combination thereof: Timed 25-FootWalking test (T25FW), Timed Up and Go (TUG), 2 minute walk test, sixminute timed walk test (6MTW), and/or, Twelve Item Multiple SclerosisWalking Scale (MSWS-12). In some embodiments, the T25FW, TUG, 2 minutewalk, 6MTW and/or MSWS-12 is significantly improved relative to placebo,as evaluated in a placebo-controlled clinical trial. In otherembodiments, the T25FW, TUG, 2 minute walk, 6MTW and/or MSWS-12 issignificantly improved in the subject relative to before beginningadministration of the composition as described herein. In someembodiments, the reduction walking impairment is measured on a numericscale that is used by or accepted by the FDA or other regulatoryagencies to evaluate the effectiveness of and to approve for licensuredrugs for the treatment of walking impairment. In some embodiments,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% improvement in one or more ofthe assessment scores described herein (such as the T25FW, TUG, 2 minutewalk, 6MTW and/or MSWS-12).

In certain embodiments of the methods for, and oral pharmaceuticalcompositions for use in, treating a hypokinetic disorder in a subjectwith Multiple Sclerosis, walking speed is improved, walking ability isimproved, overall mobility is improved, or the ability to get up isimproved in an amount as described herein after at least 6 weeks ofadministering once daily to the subject the oral pharmaceuticalcomposition, after at least 7 weeks of administering once daily to thesubject the oral pharmaceutical composition, after at least 8 weeks ofadministering once daily to the subject the oral pharmaceuticalcomposition, after at least 9 weeks of administering once daily to thesubject the oral pharmaceutical composition, after at least 10 weeks ofadministering once daily to the subject the oral pharmaceuticalcomposition, after at least 11 weeks of administering once daily to thesubject the oral pharmaceutical composition, or after at least 12 weeksof administering once daily to the subject the oral pharmaceuticalcomposition. In certain embodiments, wherein the subject is firstadministered a first composition comprising lower dose of amantadine oran equivalent amount of a pharmaceutically acceptable salt thereofduring a lead-in, titration period, walking speed is improved, walkingability is improved, overall mobility is improved, or the ability to getup is improved in an amount as described herein after at least 6 weeksof administering once daily to the subject a second oral pharmaceuticalcomposition, after at least 7 weeks of administering once daily to thesubject a second oral pharmaceutical composition, after at least 8 weeksof administering once daily to the subject a second oral pharmaceuticalcomposition, after at least 9 weeks of administering once daily to thesubject a second oral pharmaceutical composition, after at least 10weeks of administering once daily to the subject a second oralpharmaceutical composition, after at least 11 weeks of administeringonce daily to the subject a second oral pharmaceutical composition, orafter at least 12 weeks of administering once daily to the subject asecond oral pharmaceutical composition, wherein the second oralpharmaceutical composition has a higher dose of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. In someembodiments, walking speed is improved, walking ability is improved,overall mobility is improved, or the ability to get up is improvedrelative to a placebo, as evaluated in a placebo-controlled clinicalstudy. In other embodiments, walking speed is improved, walking abilityis improved, overall mobility is improved, or the ability to get up isimproved relative to the same metric in the subject before beginningadministering of the oral pharmaceutical composition. In certainembodiments, walking speed is improved, walking ability is improved,overall mobility is improved, or the ability to get up is improvedrelative to the same metric in the subject before beginningadministering of the first oral pharmaceutical composition, wherein thesubject is administered a first oral pharmaceutical composition during alead-in titration period (with a lower dose of amantadine or anequivalent amount of a pharmaceutically acceptable salt thereof) andthen a second oral pharmaceutical composition (with a higher dose ofamantadine or an equivalent amount of a pharmaceutically acceptable saltthereof).

Some embodiments described herein provide a method of increasing the ONtime without troublesome dyskinesia without increasing sleepdisturbances in a subject with Parkinson's disease comprising orallyadministering to said subject once per day, 0 to 4 hours before bedtimea composition comprising 260 to 420 mg amantadine, or an equivalentamount of a pharmaceutically acceptable salt thereof (e.g., amantadinehydrochloride), and at least one release modifying excipient. In someembodiments, the composition comprises 260 to 340 mg amantadinehydrochloride. In some such methods, the dose of amantadinehydrochloride is from 300 to 360 mg per day, particularly 330 to 350 mgper day, and in particular 340 mg per day. In some embodiments, thecomposition is administered at night.

Some embodiments described herein provide a method of improvingClinician's Global Impression without increasing sleep disturbances in asubject with Parkinson's disease comprising orally administering to saidsubject once per day, 0 to 4 hours before bedtime a compositioncomprising 260 to 420 mg amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof (e.g., amantadinehydrochloride), and at least one release modifying excipient. In someembodiments, the composition comprises 260 to 340 mg amantadinehydrochloride. In some such methods, the dose of amantadinehydrochloride is from 300 to 360 mg per day, particularly 330 to 350 mgper day, and in particular 340 mg per day. In some embodiments, thecomposition is administered at night.

Some embodiments described herein provide a method of increasing the ONtime without dyskinesia in a subject with Parkinson's disease,comprising orally administering to the subject once daily, a compositioncomprising 260 to 420 mg amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof (e.g., amantadinehydrochloride) and at least one release modifying excipient. In someembodiments, the composition comprises 260 to 340 mg amantadinehydrochloride. In some such methods, the change in ON time withoutdyskinesia is determined in a placebo controlled, double blind clinicalstudy using the PD Home Diary. In some such methods, the dose ofamantadine hydrochloride is from 300 to 360 mg per day, particularly 330to 350 mg per day, and in particular 340 mg per day. In someembodiments, the composition is administered at night. In some suchmethods, the C-ave-day is 1.2 to 1.7 times the C-ave-night; in someembodiments of the methods, the C-ave-day is measured between the hoursof 6 am to 4 pm and the C-ave-night is measured between the hours of 8pm to 5 am. In some such methods, administration of a single dose of thecomposition to a cohort of human healthy volunteer subjects in a fastedstate provides an average maximum plasma concentration (Cmax) of 1.1 to2.0 ng/ml per mg of amantadine or an AUC_(0-inf) (Area under theconcentration-curve curve from t=0 to t=infinity) of 42 to 56 ng*h/mLper mg of amantadine or both. In some such methods, the daily oraladministration of a dose of the composition to a cohort of humansubjects provides a steady state plasma concentration profilecharacterized by at least one of: (i) a mean Cmax of 2.2 to 3.1 ng/mlper mg of amantadine, (ii) a mean Cmin of 1.4 to 1.7 ng/ml per mg ofamantadine, and (iii) a mean AUC₀₋₂₄ of 43 to 72 ng*h/mL per mg ofamantadine; in more specific methods, all three criteria of (i), (ii)and (iii) are met.

Some embodiments described herein provide a method of reducing the ONtime with dyskinesia in a subject with Parkinson's disease comprisingorally administering to said subject once daily, a compositioncomprising 260 to 420 mg amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof (e.g., amantadinehydrochloride), and at least one release modifying excipient. In someembodiments, the composition comprises 260 to 340 mg amantadinehydrochloride. In some such methods, the change in ON time withdyskinesia is determined in a placebo controlled, double blind clinicalstudy using the PD Home Diary. In some such methods, the dose ofamantadine, or pharmaceutically acceptable salt thereof, is from 300 to360 mg per day, particularly 330 to 350 mg per day, and in particular340 mg per day. In some embodiments, the composition is orallyadministered at night. In some such methods, the C-ave-day is 1.2 to 1.7times the C-ave-night; in some embodiments of the methods the C-ave-dayis measured between the hours of 8 am to 4 pm and the C-ave-night ismeasured between the hours of 8 pm to 5 am. In some such methods,administration of a single dose of the composition to a cohort of humanhealthy volunteer subjects in a fasted state provides an average maximumplasma concentration (Cmax) of 1.1 to 2.0 ng/ml per mg of amantadine oran AUC_(0-inf) (Area under the concentration-curve curve from t=0 tot=infinity) of 42 to 70 ng*h/mL per mg of amantadine or both. In somesuch methods, the daily oral administration of a dose of the compositionto a cohort of human subjects provides a steady state plasmaconcentration profile characterized by at least one of: (i) a mean Cmaxof 2.2 to 3.1 ng/ml per mg of amantadine, (ii) a mean Cmin of 1.4 to 1.7ng/ml per mg of amantadine, and (iii) a mean AUC₀₋₂₄ of 43 to 70 ng*h/mLper mg of amantadine; in more specific methods, all three criteria of(i), (ii) and (iii) are met.

Some embodiments described herein provide a method of reducing the ONtime with troublesome dyskinesia in a subject with Parkinson's disease,comprising orally administering to said subject once daily, acomposition comprising 260 to 420 mg amantadine, or an equivalent amountof a pharmaceutically acceptable salt thereof (e.g., amantadinehydrochloride), and at least one release modifying excipient. In someembodiments, the composition comprises 260 to 340 mg amantadinehydrochloride. In some embodiments, the composition is orallyadministered at night. In some such methods, the change in ON timewithout troublesome dyskinesia is determined in a placebo controlled,double blind clinical study using the PD Home Diary. In some suchmethods, the dose of a pharmaceutically acceptable salt of amantadine isfrom 300 to 360 mg per day, particularly 330 to 350 mg per day, and inparticular 340 mg per day. In some such methods, the C-ave-day is 1.2 to1.7 times the C-ave-night; in some embodiments of the methods, theC-ave-day is measured between the hours of 8 am to 4 pm and theC-ave-night is measured between the hours of 8 pm to 5 am. In some suchmethods, administration of a single dose of the composition to a cohortof human healthy volunteer subjects in a fasted state provides anaverage maximum plasma concentration (Cmax) of 1.1 to 2.0 ng/ml per mgof amantadine or an AUC_(0-inf) (Area under the concentration-curvecurve from t=0 to t=infinity) of 42 to 70 ng*h/mL per mg of amantadineor both. In some such methods, the daily oral administration of a doseof the composition to a cohort of human subjects provides a steady stateplasma concentration profile characterized by at least one of: (i) amean Cmax of 2.2 to 3.0 ng/ml per mg of amantadine, (ii) a mean Cmin of1.4 to 1.7 ng/ml per mg of amantadine, and (iii) a mean AUC₀₋₂₄ of 42 to69 ng*h/mL per mg of amantadine; in more specific methods, all threecriteria of (i), (ii) and (iii) are met.

Some embodiments described herein provide a method of reducing the OFFtime in a subject with Parkinson's disease comprising orallyadministering to said subject once daily, a composition comprising 260to 340 mg amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof (e.g., amantadine hydrochloride), and at leastone release modifying excipient. In some embodiments, the compositioncomprises 260 to 340 mg amantadine hydrochloride. In some such methods,the change in OFF time is determined in a placebo controlled, doubleblind clinical study using the PD Home Diary. In some such methods, thedose of a pharmaceutically acceptable salt of amantadine, is from 300 to360 mg per day, particularly 330 to 350 mg per day, and in particular340 mg per day. In some such methods, the C-ave-day is 1.4 to 1.7 timesthe C-ave-night; in some embodiments of the methods, the C-ave-day ismeasured between the hours of 8 am to 8 pm and the C-ave-night ismeasured between the hours of 8 pm to 8 am. In some such methods,administration of a single dose of the composition to a cohort of humanhealthy volunteer subjects in a fasted state provides an average maximumplasma concentration (Cmax) of 1.1 to 1.7 ng/ml per mg of amantadine oran AUC_(0-inf) (Area under the concentration-curve curve from t=0 tot=infinity) of 46 to 56 ng*h/mL per mg of amantadine or both. In somesuch methods, the daily oral administration of a dose of the compositionto a cohort of human subjects provides a steady state plasmaconcentration profile characterized by at least one of: (i) a mean Cmaxof 2.2 to 2.7 ng/ml per mg of amantadine, (ii) a mean Cmin of 1.4 to 1.7ng/ml per mg of amantadine, and (iii) a mean AUC₀₋₂₄ of 46 to 56 ng*h/mLper mg of amantadine; in more specific methods, all three criteria of(i), (ii) and (iii) are met.

Some embodiments described herein provide a method of increasing the ONtime without troublesome dyskinesia without increasing sleepdisturbances in a subject with Parkinson's disease comprising orallyadministering to said subject once daily, a composition comprising 260to 420 mg amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof (e.g., amantadine hydrochloride), and at leastone release modifying excipient. In some embodiments, the compositioncomprises 260 to 340 mg amantadine hydrochloride. In some such methods,the dose of a pharmaceutically acceptable salt of amantadine, such asamantadine hydrochloride, is from 300 to 360 mg per day, particularly330 to 350 mg per day, and in particular 340 mg per day. In some suchmethods, the C-ave-day is 1.2 to 1.7 times the C-ave-night; in someembodiments of the methods, the C-ave-day is measured between the hoursof 8 am to 4 pm and the C-ave-night is measured between the hours of 8pm to 5 am. In some such methods, administration of a single dose of thecomposition to a cohort of human healthy volunteer subjects in a fastedstate provides an average maximum plasma concentration (Cmax) of 1.1 to2.0 ng/ml per mg of amantadine or an AUC_(0-inf) (Area under theconcentration-curve curve from t=0 to t=infinity) of 42 to 69 ng*h/mLper mg of amantadine or both. In some such methods, the daily oraladministration of a dose of the composition to a cohort of humansubjects provides a steady state plasma concentration profilecharacterized by at least one of: (i) a mean Cmax of 2.2 to 3.1 ng/mlper mg of amantadine, (ii) a mean Cmin of 1.4 to 1.7 ng/ml per mg ofamantadine, and (iii) a mean AUC₀₋₂₄ of 42 to 69 ng*h/mL per mg ofamantadine; in more specific methods, all three criteria of (i), (ii)and (iii) are met.

Some embodiments described herein provide a method of improvingClinician's Global Impression without increasing sleep disturbances in asubject with Parkinson's disease comprising orally administering to saidsubject once daily, a composition comprising 260 to 420 mg amantadine,or an equivalent amount of a pharmaceutically acceptable salt thereof(e.g., amantadine hydrochloride), and at least one release modifyingexcipient. In some embodiments, the composition comprises 260 to 340 mgamantadine hydrochloride, or an equivalent amount of a pharmaceuticallyacceptable salt thereof. In some such methods, the dose of apharmaceutically acceptable salt of amantadine, such as amantadinehydrochloride, is from 300 to 360 mg per day, particularly 330 to 350 mgper day, and in particular 340 mg per day. In some such methods, theC-ave-day is 1.2 to 1.7 times the C-ave-night; in some embodiments ofthe methods, the C-ave-day is measured between the hours of 8 am to 4 pmand the C-ave-night is measured between the hours of 8 pm to 5 am. Insome such methods, administration of a single dose of the composition toa cohort of human healthy volunteer subjects in a fasted state providesan average maximum plasma concentration (Cmax) of 1.1 to 2.0 ng/ml permg of amantadine or an AUC_(0-inf) (Area under the concentration-curvecurve from t=0 to t=infinity) of 42 to 69 ng*h/mL per mg of amantadineor both. In some such methods, the daily oral administration of a doseof the composition to a cohort of human subjects provides a steady stateplasma concentration profile characterized by at least one of: (i) amean Cmax of 2.2 to 3.1 ng/ml per mg of amantadine, (ii) a mean Cmin of1.4 to 1.7 ng/ml per mg of amantadine, and (iii) a mean AUC₀₋₂₄ of 42 to69 ng*h/mL per mg of amantadine; in more specific methods, all threecriteria of (i), (ii) and (iii) are met.

The disclosure also provides a method of reducing gastrointestinal (GI)adverse events in a subject undergoing treatment with amantadine. Themethod comprises orally administering a composition comprisingamantadine, or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, such that the frequency of GI adverse events (asdetermined from single dose, fasting human pharmacokinetic studies) isless than 19.5%; preferably less than 17.5%, and more preferably lessthan 12.5%. In some embodiments, a low incidence of gastrointestinaladverse events includes less than 12%, less than 10%, less than 8%, lessthan 7%, less than 6%, less than 5%, less than 4%, less than 3%, lessthan 2%, or less than 1% of the subjects of a fasted, single dose humanpharmacokinetic study experiencing at least one gastrointestinal adverseevent. In some embodiments, the gastrointestinal effects are selectedfrom the group consisting of abdominal distension, constipation,diarrhea, dyspepsia, gingival pain, dry lip, lower abdominal pain,nausea, stomach discomfort, toothache, upper abdominal pain, andvomiting In some embodiments, the composition comprises less than 6000ppm of organic solvent. In certain embodiment, the composition comprisesless than 5500 ppm, less than 5000 ppm, less than 4500 ppm, less than4000 ppm, less than 3500 ppm, less than 3000 ppm, less than 2500 ppm,less than 2000 ppm, less than 1500 ppm, or less than 1200 ppm organicsolvent. In some embodiments, the composition comprises a plurality ofcoated core seeds, wherein each coated core seed comprises a core seedsurrounded by a drug coating, and the plurality of coated core seedscomprises less than 6000 ppm, less than 5500 ppm, less than 5000 ppm,less than 4500 ppm, less than 4000 ppm, less than 3500 ppm, less than3000 ppm, less than 2500 ppm, less than 2000 ppm, less than 1500 ppm, orless than 1200 ppm organic solvent. In some embodiments, the organicsolvent is a linear or cyclic ketone (e.g., acetone, methyl ethylketone, etc.) In some embodiments, the organic solvent is a sulfoxide(e.g., dimethyl sulfoxide, etc). In some embodiments, the organicsolvent is an amide (e.g., dimethyl formamide, N-methyl pyrrolidone,hexamethyl phosphorous triamide (HMPT), etc.). In some embodiments, theorganic solvent is a linear or cyclic ether (e.g., tetrahydrofuran,diethyl ether, bis(2-methoxyethyl) ether (diglyme), dimethoxy ethane(glyme), 1,4-dioxane, etc.). In some embodiments, the organic solvent isa phosphoramide (e.g., hexamethyl phosphoramide (HPMA), etc.). In someembodiments, the organic solvent is a chlorinated hydrocarbon (e.g.,chloroform, dichloromethane, dichloro ethane, carbon tetrachloride,etc.). In some embodiments, the organic solvent is a glycol (e.g.,ethylene glycol, diethylene glycol, propylene glycol, etc.). In someembodiments, the organic solvent is a, nitrogen-containing solvent(e.g., pyridine, acetonitrile, etc.). In some embodiments, the organicsolvent is an alcohol (e.g., a C₁-C₆ alcohol (e.g., ethanol, methanol,isopropanol, 1-butanol, 2-butanol, glycerol), such as isopropyl alcohol.In some embodiments, mixtures of two or more solvents can be used. Insome embodiments of the levels of organic solvent described herein, theprovided level refers to the total amount of two or more organicsolvents. In some embodiments, the daily dose of amantadine is 170 mg to340 mg, or an equivalent amount of a pharmaceutically acceptable saltthereof; preferably the daily dose comprises 170 mg to 340 mg ofamantadine hydrochloride, or an equivalent amount of a pharmaceuticallyacceptable salt thereof. In some such methods, the C-ave-day is 1.2 to1.7 times the C-ave-night; in some embodiments of the methods, theC-ave-day is measured between the hours of 8 am to 4 pm and theC-ave-night is measured between the hours of 8 pm to 5 am. In some suchmethods, administration of a single dose of the composition to a cohortof human healthy volunteer subjects in a fasted state provides anaverage maximum plasma concentration (Cmax) of 1.1 to 2.0 ng/ml per mgof amantadine or an AUC_(0-inf) (Area under the concentration-curvecurve from t=0 to t=infinity) of 42 to 69 ng*h/mL per mg of amantadineor both. In some such methods, the daily oral administration of a doseof the composition to a cohort of human subjects provides a steady stateplasma concentration profile characterized by at least one of: (i) amean Cmax of 2.2 to 3.0 ng/ml per mg of amantadine, (ii) a mean Cmin of1.4 to 1.7 ng/ml per mg of amantadine, and (iii) a mean AUC₀₋₂₄ of 42 to69 ng*h/mL per mg of amantadine; in more specific methods, all threecriteria of (i), (ii) and (iii) are met.

The disclosure also provides a method of reducing sleep disturbances ina subject undergoing treatment with amantadine, or a pharmaceuticallyacceptable salt thereof. The method comprises orally administeringamantadine, or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, such that the amantadine or pharmaceutically acceptablesalt thereof does not interfere with sleep, yet provides maximum benefitin morning hours. Morning hours may include, for example, from the hourof 5 am, 6 am, 7 am, 8 am or 9 am to the hour of 11 am, 11:30 am, 12 pm,12:30 pm or 1:00 pm. In some embodiments, the method provides nighttimecoverage of symptoms of Parkinson's. Nighttime coverage may includeproviding benefit if the subject wakes up and wishes to return to sleep.In some such methods, the C-ave-day is 1.2 to 1.7 times the C-ave-night;in some embodiments of the methods, the C-ave-day is measured betweenthe hours of 8 am to 4 pm and the C-ave-night is measured between thehours of 8 pm to 5 am. In some such methods, administration of a singledose of the composition to a cohort of human healthy volunteer subjectsin a fasted state provides an average maximum plasma concentration(Cmax) of 1.1 to 2.0 ng/ml per mg of amantadine or an AUC_(0-inf) (Areaunder the concentration-curve curve from t=0 to t=infinity) of 42 to 69ng*h/mL per mg of amantadine or both. In some such methods, the dailyoral administration of a dose of the composition to a cohort of humansubjects provides a steady state plasma concentration profilecharacterized by at least one of: (i) a mean Cmax of 2.2 to 3.0 ng/mlper mg of amantadine, (ii) a mean Cmin of 1.4 to 1.7 ng/ml per mg ofamantadine, and (iii) a mean AUC₀₋₂₄ of 42 to 69 ng*h/mL per mg ofamantadine; in more specific methods, all three criteria of (i), (ii)and (iii) are met.

In some embodiments, the methods provided herein comprise orallyadministering to a subject an extended release (ER) compositioncomprising amantadine, or a pharmaceutically acceptable salt thereof,formulated for nighttime administration. The composition may be a lessthan three hours before bedtime, and preferably less than two and ahalf, less than two, less than one and a half, or less than one hourbefore bedtime. Most preferably the ER composition is taken less thanhalf hour before bedtime (e.g., the time at which the subject wishes togo to sleep). Alternatively, the composition is administered less thanabout 4 hours before bedtime.

As used herein, “extended release” includes “controlled release”,“modified release”, “sustained release”, “timed release”, “delayedrelease”, and also mixtures of delayed release, immediate release,enteric coated, etc. with each of the above.

The methods included herein include orally administering to a subject apharmaceutical composition comprising amantadine or a pharmaceuticallyacceptable salt thereof. The subject may be diagnosed with any diseaseor disorder for which amantadine or a pharmaceutically acceptable saltthereof is prescribed, such as Parkinson's disease, multiple sclerosis,drug-induced extrapyramidal reactions, levodopa-induced dyskinesia, or aviral disease (e.g., influenza, HBV, or HCV). In a specific embodiment,the subject has Parkinson's disease, which, as used herein, alsoencompasses a diagnosis of parkinsonism. In some embodiments, thesubject has early stage Parkinson's disease, and the pharmaceuticalcomposition as described herein is used as a monotherapy or incombination with a monoamine oxidase type B (MAO-B) inhibitor withoutconcomitant use of levodopa. In another embodiment, the subject has latestage Parkinson's disease and the subject takes levodopa in addition toa pharmaceutical composition as described herein. In another embodiment,the subject has multiple sclerosis and the pharmaceutical composition asdescribed herein is used for the treatment of fatigue. In otherembodiments, the subject has a brain injury, brain injury, brain trauma,dementia, Alzheimer's disease, stroke, Huntington's disease, ALS,Multiple Sclerosis, neurodegenerative diseases, dementias,cerebrovascular conditions, movement disorders, cranial nerve disorders,or a neuropsychiatric disorder.

The oral pharmaceutical compositions provided herein, and for use in themethods described herein, may be formulated for oral nighttimeadministration to provide a plasma concentration profile that does notinterfere with the subject's sleep. The composition of the disclosuremay, upon administration to a human subject, result in a gradual initialincrease in plasma concentration of amantadine such that, at steadystate conditions, administration of a dose of the composition results inan increase in plasma concentration of amantadine of less than 25% atthree hours after the dose is administered. For example, if a subject'ssteady state plasma concentration of amantadine is 500 ng/ml at the timea dose of the composition is administered, three hours later thesubject's plasma concentration of amantadine may be less than 625 ng/ml.Preferably, the increase in plasma concentration of amantadine threehours after administration of an oral pharmaceutical composition asdescribed herein is less than 15%, and most preferably, less than 10%.In certain embodiments, the compositions have a plasma concentrationprofile further characterized by no increase in amantadine plasmaconcentration, or even a decrease (at steady state conditions), for atleast one or, in some embodiments, two hours after the administration.The compositions provided herein, and for use in the methods providedherein, may be adapted for bedtime (e.g., the time at which the subjectwishes to go to sleep) administration by providing a maximumconcentration of amantadine (Cmax) in the morning hours. The time toreach Cmax (Tmax), as measured after single dose administration in thefasted state, may be at least 9 hours and up to 15, 16, 17, or 18 hours,or at least 10 hours and up to 14, 15, 16, 17, or 18 hours, or at least12 hours, and up to 14, 15, 16, or 17 hours. In specific embodiments,the Tmax may be 9 to 18 hours, most preferably 12 to 18 hours. At steadystate, with once nightly administration of the composition, the Tmax maybe 7 to 13 hours, most preferably 8 to 12 hours. A suitable ERamantadine composition may have a steady-state Cmax/Cmin ratio of 1.3 to1.8, and preferably 1.4 to 1.7, resulting in a composition with dailyprofile.

In other embodiments, the plasma concentration profile has an AUCprofile after administration of a single dose of the compositionwherein: the fractional AUC from 0 to 4 hours is less than 5%, andpreferably less than 3% of AUC_(0-inf); the fractional AUC from 0 to 8hours is about 5 to 15%, and preferably about 8 to 12% of AUC_(0-inf);the fractional AUC from 0 to 12 hours is about 10 to 40%, and preferablyabout 15 to 30% of AUC_(0-inf); the fractional AUC from 0 to 18 hours isabout 25 to 60%, and preferably about 30 to 50% of AUC_(0-inf); and thefractional AUC from 0 to 24 hours is about 40 to 75%, and preferablyabout 50 to 70% of AUC_(0-inf).

In further embodiments, the plasma concentration profile of thepharmaceutical composition has an AUC profile after once nightly dosingof the composition at steady state conditions wherein: the fractionalAUC from 0 to 4 hours is about 2 to 25%, and preferably about 5 to 20%of AUC₀₋₂₄; the fractional AUC from 0 to 8 hours is about 15 to 50%, andpreferably about 20 to 40% of AUC₀₋₂₄; the fractional AUC from 0 to 12hours is about 30 to 70%, and preferably about 40 to 60% of AUC₀₋₂₄; andthe fractional AUC from 0 to 18 hours is about 60 to 95%, and preferablyabout 75 to 90% of AUC_(0-24.)

In some embodiments of any of the aspects herein, the steady stateplasma concentration profile following multiple oral administrations toa human subject of the composition at bedtime is characterized by anaverage plasma concentration during the day (“C-ave-day”, defined as theaverage day time amantadine plasma concentration as measured in a humanPK study) that is 1.1 to 2.0 times the average plasma concentrationduring the night (“C-ave-night”, defined as the average night timeamantadine plasma concentration as measured in a human PK study). Insome embodiments, the ratio of C-ave-day/C-ave-night at steady state iswithin one of the ranges 1.3 to 1.9, 1.3 to 1.8, 1.3 to 1.7, 1.3 to 1.6,1.4 to 1.9, 1.4 to 1.8, 1.4 to 1.7, 1.5 to 1.9, 1.5 to 1.8, 1.5 to 1.7,or 1.6 to 1.9. In some embodiments, the ratio of C-ave-day/C-ave-nightat steady state is 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7,1.75, 1.8, 1.85, or 1.9. In some embodiments, the C-ave-day is theaverage amantadine plasma concentration as measured between the hours of5 am, 6 am, 7 am, 8 am or 9 am to the hours of 4 pm, 5 pm, 6 pm, 7 pm or8 pm and the C-ave-night is the average amantadine plasma concentrationas measured between the hours of 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, 9 pm, 10pm or 11 pm to the hours of 4 am, 5 am, 6 am, 7 am, 8 am or 9 am. Insome embodiments, the C-ave-day is the average amantadine plasmaconcentration as measured within any four to twelve hour period betweenthe hours of 5 am and 8 pm; and the C-ave-night is the averageamantadine plasma concentration as measured within any four to twelvehour period between the hours of 8 pm and 5 am. In some embodiments, theC-ave-day is the average amantadine plasma concentration as measuredwithin any four, five, six, seven, eight, nine, ten, eleven or twelvehour period between the hours of 5 am and 8 pm; and the C-ave-night isthe average amantadine plasma concentration as measured within any four,five, six, seven, eight, nine, ten, eleven or twelve hour period betweenthe hours of 8 pm and 4 am.

In some embodiments described herein the pharmaceutical composition isadministered to a subject from 0 to 4 hours prior to bedtime. In someembodiments, the pharmaceutical composition is administered to a subjectfrom 0 to 3, 0 to 2, or 0 to 1 hours prior to bedtime. In someembodiments, the pharmaceutical composition is administered to a subjectfrom 0 to 240 minutes, from 0 to 180 minutes, e.g., from 0 to 120minutes, from 0 to 60 minutes, from 0 to 45 minutes, from 0 to 30minutes, from 0 to 15 minutes or from 0 to 10 minutes prior to bedtime.In some embodiments, the pharmaceutical composition is administered to asubject from 60 to 240 minutes, from 60 to 180 minutes, from 60 to 120minutes or from 60 to 90 minutes prior to bedtime.

It is to be understood that administration to a subject includesadministration by a healthcare professional and self-administration bythe subject.

Unless otherwise specified herein, the term “bedtime” described when aperson retires for the primary sleep period during a twenty-four hourperiod of time. While for the general populace, bedtime occurs at night,there are subjects, such as those who work nights, for whom bedtimeoccurs during the day. Thus, in some embodiments, bedtime may be anytimeduring the day or night.

As used herein, unless otherwise indicated, reference to a plasmaconcentration profile or a specific pharmacokinetic property (e.g.,Cmax, Cmin, AUC, Tmax, etc.) in a human subject refers to a mean valueobtained from healthy adults determined in a typical phase I clinicaltrial designed to measure pharmacokinetic properties of a drug (seee.g., Example 4 below); and, unless indicated otherwise, a single dose,fasting human pharmacokinetic study is dosed in the morning following anovernight fast. References herein to Tmax and T_(1/2) refer to medianand mean values, respectively, obtained after administration of a singledose at fasted states, unless otherwise indicated.

As described herein, the unit doses of the amantadine orpharmaceutically acceptable salt thereof orally administered inaccordance with the methods provided herein may be generally higher thanthe ranges normally prescribed for immediate release compositionscomprising amantadine or a pharmaceutically acceptable salt thereof. Forexample, the recommended dose of amantadine for the treatment ofParkinson's disease is 100 mg immediate release amantadine administeredtwice daily, or an equivalent amount of a pharmaceutically acceptablesalt thereof. In limited cases of the subject not deriving sufficientbenefit at that dose, and subject to the subject being able to toleratea higher dose, the daily dose may be increased to 300 mg or 400 mg, oran equivalent amount of a pharmaceutically acceptable salt thereof,which is always administered in divided doses. The most commonlyprescribed dose of amantadine is 200 mg per day, or an equivalent amountof a pharmaceutically acceptable salt thereof, is always administered individed doses. More than 200 mg (for example 300 mg) was always given individed doses. In contrast, the present methods may includeadministration of 260 to 420 mg of amantadine, or an equivalent amountof a pharmaceutically acceptable salt, for treatment of a subject withParkinson's disease, and the methods and compositions of the disclosuremay comprise once-nightly administration of a dose as defined by any ofthese ranges, particularly at doses from 260 mg to 420 mg, and mostpreferably 340 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof, once per day. In some suchembodiments the administration of such higher doses is at night, e.g.,after 4 p.m. and/or within 4 hours of bedtime. In additionalembodiments, the administration of such higher doses may be in the formof 1, 2 or 3 capsules of size 0, 1 or 2 in the normal or EL formatadministered once nightly.

In some embodiments of any of the aspects herein the amantadine isadministered as a pharmaceutically acceptable salt. In a more specificembodiment, the amantadine is administered as amantadine hydrochlorideor amantadine sulfate.

In some embodiments of any of the aspects herein, a total daily dose of260 mg to 420 mg of amantadine or an equivalent amount of apharmaceutically acceptable salt thereof is administered as aformulation after 4 p.m. and/or within 4 hours of bedtime. In someembodiments, the dose of amantadine or pharmaceutically acceptable saltthereof exceeds 300 mg per day. In various specific embodiments, thetotal dose of amantadine administered per day may be 260 to 275 mg, 270to 285 mg, 280 to 295 mg, 290 to 305 mg, 300 to 315 mg, 310 to 325 mg,320 to 335 mg, 330 to 345 mg, 340 to 355 mg, 350 to 365 mg, 360 to 375mg, 370 to 385 mg, 380 to 395 mg, 390 to 405 mg, 400 to 415 mg, or 410to 420 mg, or the dose may be an equivalent amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, the total dose ofamantadine administered per day is 260 mg to 360 mg, 300 to 360 mg, 330to 350 mg or 340 mg, or an equivalent amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, the dose of apharmaceutically acceptable salt of amantadine, such as amantadinehydrochloride, is 300 to 360 mg, 330 to 350 mg or 340 mg. As describedherein, the dose may be a single daily dose, and may be administered atnight, for example after 4 pm.

In some embodiments of any of the aspects herein, the total once dailydose of amantadine administered is from about 260 mg, 265 mg, 270 mg,275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg, or an equivalentamount of a pharmaceutically acceptable salt of amantadine; to about 305mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395mg, 400 mg, 405 mg, 410 mg, 415 mg, or 420 mg, or an equivalent amountof a pharmaceutically acceptable salt of amantadine.

In still further embodiments of any of the aspects herein, such asmethods of increasing the ON time without dyskinesia in a subject withParkinson's disease; reducing the ON time with dyskinesia in a subjectwith Parkinson's disease; reducing the ON time with troublesomedyskinesia in a subject with Parkinson's disease; reducing the OFF timein a subject with Parkinson's disease; treating a hypokinetic disorderin a subject with Multiple Sclerosis; reducing gastrointestinal (GI)adverse events in a subject undergoing treatment with amantadine or apharmaceutically acceptable salt thereof; or reducing sleep disturbancesin a subject undergoing treatment with amantadine or a pharmaceuticallyacceptable salt thereof, the total once daily dose of amantadineadministered is about 68.5 mg, about 137 mg, about 205.5 mg, about 274mg of amantadine, from about 60 mg to about 80 mg, from about 120 mg toabout 155 mg, from about 185 mg to about 230 mg, or from about 245 mg toabout 305 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In some embodiments, the totalonce daily dose administered is about 85 mg, about 170 mg, about 255 mg,about 340 mg from about 75 mg to about 95 mg, from about 150 mg to about190 mg, from about 230 mg to about 285 mg, or from about 305 to about375 mg of amantadine hydrochloride. In some embodiments, the once dailydose is administered at night. In certain embodiments, the once dailydose is administered from 0 to 4 hours before bedtime, or from 0 to 3hours before bedtime. In certain embodiments, the once daily dose isadministered in the day. In some embodiments, the total daily dose isadministered as 1, 2, or 3 separate dosage units, such as separatecapsules. In certain embodiments, each dosage unit comprises about 68.5mg, about 137 mg, from about 60 mg to about 155 mg, from about 60 mg toabout 80 mg, or from about 120 mg to about 155 mg amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. Incertain embodiments, each dosage unit comprises about 85 mg, about 170mg, from about 75 mg to about 190 mg, from about 75 mg to about 95 mg,or from about 150 mg to about 190 mg of amantadine hydrochloride. Incertain embodiments, two or more dosage units comprising differentamounts of amantadine or pharmaceutically acceptable salt thereof areadministered, for example, one or more dosage units comprising about68.5 mg, or from about 60 mg to about 155 mg amantadine or equivalentamount of a pharmaceutically acceptable salt thereof, and one or moredosage units comprising about 137 mg, or from about 120 mg to about 155mg amantadine or an equivalent amount of a pharmaceutically acceptablesalt thereof.

In specific embodiments described herein, a subject's entire daily doseof amantadine or a pharmaceutically acceptable salt thereof isadministered once, during a period of less than about four, three, twoor one hours before bedtime (e.g., after 4 p.m., or the time at whichthe subject wishes to go to sleep).

In some embodiments of any of the aspects herein, oral administration ofthe composition to a subject with Parkinson's disease results in asignificant reduction in one or more Parkinson's disease symptoms ormotor fluctuations. In some specific embodiments, administration of thecomposition results in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%reduction in one or more Parkinson's disease symptoms or motorfluctuations. In further specific embodiments, the reduction inParkinson's symptoms or motor fluctuations is measured on a numericalscale used by or accepted by the FDA or other regulatory agencies toevaluate the effectiveness of and to approve for licensure drugs for thetreatment of Parkinson's symptoms or motor fluctuations. In furtherspecific embodiments, the scale used in measuring the reduction inParkinson's symptoms motor fluctuations could be the Unified Parkinson'sDisease Rating Scale (UPDRS). Unified Parkinson's Disease Rating Scale(UPDRS, MDS revision)—Part I: non-motor aspects of experiences of dailyliving (13 items), —Part II: motor aspects of experiences of dailyliving (13 items)—Part III: motor examination (33 scored items), Hoehnand Yahr Staging Scale (Original or Modified), or PD Home Diary: totalON time or total OFF time.

In some embodiments of any of the aspects herein, oral administration ofthe composition to a subject with Parkinson's disease results in asignificant reduction in levodopa induced dyskinesia. In a specificembodiment, administration of the composition results in about 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80%reduction in levodopa induced dyskinesia. In further embodiments, thereduction in levodopa induced dyskinesia is measured on a numeric scalethat is used by or accepted by the FDA or other regulatory agencies toevaluate effectiveness of and to approve for licensure drugs for thetreatment of LID. In further specific embodiments, the scale used inmeasuring the reduction in LID could be UDysRS, UPDRS Part IV (subscores32, 33), MDS-UPDRS Part IV, total and items 4.1 and 4.2, DyskinesiaRating Scale (DRS), Abnormal Involuntary Movement Scale (AIMS), RushDyskinesia Rating Scale, Parkinson Disease Dyskinesia Scale (PDYS-26),Obeso Dyskinesia Rating Scale (CAPIT), Clinical Dyskinesia Rating Scale(CDRS), Lang-Fahn Activities of Daily Living Dyskinesia or other scalesdeveloped for this purpose. In other specific embodiments, the reductionin LID is measured relative to placebo in a controlled clinical trial.In other embodiments, the reduction in LID is measured relative tobaseline in a controlled clinical trial.

In some embodiments of any of the aspects herein, oral administration ofthe composition to a subject with Parkinson's disease results in asignificant reduction in Parkinson's disease fatigue. In a specificembodiment, administration of the composition results in about 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% reduction inParkinson's disease fatigue. In further specific embodiments, thereduction fatigue is measured on a numeric scale that is used by oraccepted by the FDA or other regulatory agencies to evaluate theeffectiveness of and to approve for licensure drugs for the treatment offatigue. In further specific embodiments, the scale used in measuringthe reduction in fatigue could be the Fatigue Severity Scale (FSS),Fatigue Assessment Inventory, Functional Assessment of Chronic IllnessTherapy-Fatigue (FACIT Fatigue), Multidimensional Fatigue Inventory(MFI-20), Parkinson Fatigue Scale (PFS-16) and the Fatigue SeverityInventory. In other specific embodiments, the reduction in fatigue ismeasured relative to placebo in a controlled clinical trial. In otherembodiments, the reduction in fatigue is measured relative to baselinein a controlled clinical trial.

In some embodiments of any of the aspects herein, oral administration ofthe composition to a subject results in a significant improvement inclinicians overall impression. In some specific embodiments,administration of the composition results in about a 0.5, 1.0, 1.5, 2.0,2.5 or 3.0 point improvement in clinicians overall impression using a 7point scale (or proportionate changes using a different scale). Infurther specific embodiments, the improvement in clinicians overallimpression is measured on a numeric scale that is used by or accepted bythe FDA or other regulatory agencies to evaluate the effectiveness ofand to approve for licensure drugs indicated for subjects withParkinson's disease. In further specific embodiments, the scale used inmeasuring the improvement in clinicians overall impression could be theClinicians Global Impression of Change Rating Scale (CGIC). In otherspecific embodiments, the improvement in clinicians overall impressionis measured relative to placebo in a controlled clinical trial. In otherembodiments, the improvement in clinicians overall impression ismeasured relative to baseline in a controlled clinical trial.

II. Pharmaceutical Composition Formulations

As described herein, provided herein are oral pharmaceuticalcompositions comprising amantadine, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient. For example,the pharmaceutical composition may be administered orally; may besuitable for, formulated for, or intended for oral delivery; or suitablefor, formulated for, or intended for oral administration. In certainembodiments, the pharmaceutical composition is an extended releaseformulation.

Extended release oral pharmaceutical compositions suitable for use inthe methods described herein can be made using a variety of extendedrelease technologies, such as those described in the patent publicationsreferenced in the above background section, which publications areincorporated herein by reference in their entireties. In someembodiments, the pharmaceutical composition comprises apellet-in-capsule dosage form. In some embodiments, the pellets are aplurality of coated core seeds, wherein each coated core seed comprise acore seed, a drug coating surrounding the core seed, and an extendedrelease coating surrounding the drug coating. In some embodiments, oneor more additional coatings are present. For example, in someembodiments, the core seed further comprises a seal coating surroundingthe drug coating, wherein the seal coating is surrounded by the extendedrelease coating.

The drug coating may comprise amantadine, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptableexcipients. In some embodiments, the one or more pharmaceuticallyacceptable excipients comprise one or more binders, or one or moreanti-tack agents, or any combinations thereof.

The extended release coating may comprise one or more release modifyingexcipients. In some embodiments, the extended release coating furthercomprises one or more plasticizers, or one or more pore-forming agents,or any combinations thereof. In certain embodiments, the one or morerelease modifying excipients comprise ethyl cellulose, and the one ormore pore-forming agent comprise povidone, HPMC, or Eudragit, orcombinations thereof.

The seal coating may comprise at one or more film-forming polymers. Theseal coating may further comprise one or more anti-tack agents, one ormore binders, or any combinations thereof. In some embodiments, the oneor more film-forming polymers comprise HPMC, copovidone, or povidone, orcombinations thereof.

In some embodiments, the coated core seed comprises more than one drugcoating, or more than one extended release coating, or a combinationthereof. For example the coated core seed may comprise a first drugcoating surrounding the core seed, a seal coating surrounding the firstdrug coating, an additional drug coating surrounding the seal coating,and an extended release coating surrounding the seal coating. In anotherexample, the coated core seed comprises a drug coating surrounding thecore seed, a first extended release coating surrounding the drugcoating, and an additional extended release coating surrounding thefirst extended release coating. The first and additional extendedrelease coatings may, for example, comprise different components, ordifferent ratios of components, or a combination thereof.

It should be understood that one or more of the coatings describedherein, for example the drug coating, the seal coating, or the extendedrelease coating, may in some embodiments fully surround the core seed,and in other embodiments surround almost all of the core seed, or themajority of the core seed, for example wherein at least 90%, at least95%, at least 98%, at least 99%, or at least 99.9% of the surface areathe core seed is surrounded by the coating. One or more of the coatingsmay be of uniform thickness, or may vary in thickness.

In some embodiments, the oral pharmaceutical composition comprises aplurality of coated core seeds. In some embodiments, the coated coreseeds have an average diameter of, for example, 300 to 1700 microns, or500 to 1200 microns. The core seeds of the coated core seeds maycomprise for example, one or more inert compounds, such as sugar (e.g.,sucrose), microcrystalline cellulose, or starch. In some embodiments,the core seed is generally spherical in shape. In some embodiments, thecore seed is a sphere. In some embodiments, the core seed is generallyovoid in shape. In some embodiments, the core seed is an ovoid. Incertain embodiments, the core seed comprises sugar (for example,sucrose), a microcrystalline cellulose (MCC), or a starch. In certainembodiments, the core seeds have an average diameter of 300 to 500microns. In some embodiments, the coated core seeds can be prepared byprocesses such as pelletization, extrusion, spheronization, etc. orcombinations thereof.

In some embodiments, the coated core seeds comprise less than 6000 ppm,less than 5500 ppm, less than 5000 ppm, less than 4500 ppm, less than4000 ppm, less than 3500 ppm, less than 3000 ppm, less than 2500 ppm,less than 2000 ppm, less than 1500 ppm, or less than 1200 ppm organicsolvent. In certain embodiments, the organic solvent is alcohol, such asisopropyl alcohol. Thus, in some embodiments, the coated core seedscomprise less than 6000 ppm of an organic solvent, such as alcohol, forexample isopropyl alcohol. As described herein, in some embodiments thecoated core seeds comprise one or more drug coatings, one or moreextended release coatings, and one or more seal coatings. In someembodiments, the organic solvent is a linear or cyclic ketone (e.g.,acetone, methyl ethyl ketone, etc.) In some embodiments, the organicsolvent is a sulfoxide (e.g., dimethyl sulfoxide, etc). In someembodiments, the organic solvent is an amide (e.g., dimethyl formamide,N-methyl pyrrolidone, hexamethyl phosphorous triamide (HMPT), etc.). Insome embodiments, the organic solvent is a linear or cyclic ether (e.g.,tetrahydrofuran, diethyl ether, bis(2-methoxyethyl) ether (diglyme),dimethoxy ethane (glyme), 1,4-dioxane, etc.). In some embodiments, theorganic solvent is a phosphoramide (e.g., hexamethyl phosphoramide(HPMA), etc.). In some embodiments, the organic solvent is a chlorinatedhydrocarbon (e.g., chloroform, dichloromethane, dichloro ethane, carbontetrachloride, etc.). In some embodiments, the organic solvent is aglycol (e.g., ethylene glycol, diethylene glycol, propylene glycol,etc.). In some embodiments, the organic solvent is a,nitrogen-containing solvent (e.g., pyridine, acetonitrile, etc.). Insome embodiments, the organic solvent is an alcohol (e.g., a C₁-C₆alcohol (e.g., ethanol, methanol, isopropanol, 1-butanol, 2-butanol,glycerol), such as isopropyl alcohol. In some embodiments, mixtures oftwo or more solvents can be used. In some embodiments of the levels oforganic solvent described herein, the provided level refers to the totalamount of two or more organic solvents.

It should be understood that while some embodiments of the compositionsdescribed herein comprise less than a certain level of organic solvent(such as less than 6,000 ppm, or less than 2,000 ppm), organic solventmay, in some embodiments, be used in one or more steps duringmanufacture of the composition. In certain embodiments, the solventlevel present during one or more of the steps of manufacture may behigher than the solvent level present in the final composition.

A. Drug Coating

The coated core seeds comprise a core seed and a drug coatingsurrounding the core seed, wherein the drug coating comprises amantadineor a pharmaceutically acceptable salt thereof. The drug coating mayfurther comprise one or more pharmaceutically acceptable excipients,such as one or more binders, or one or more anti-tack agents. In someembodiments, the drug coating comprises one or more binders selectedfrom the group consisting of hydroxypropyl methyl cellulose, copovidone,povidone, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, and carboxymethyl cellulose. In some embodiments, the drugcoating comprises one or more anti-tack agents. For example, the drugcoating may comprise one or more anti-tack agents selected from thegroup consisting of magnesium stearate, calcium silicate, magnesiumsilicate, colloidal silicon dioxide, and talc. In some embodiments, thedrug coating comprises one or more anti-tack agents selected from thegroup consisting of talc and magnesium stearate. In certain embodiments,the drug coating comprises one or more additional excipients.

In some embodiments, the drug coating comprises amantadine, or apharmaceutically acceptable salt thereof, one or more pharmaceuticallyacceptable excipients; and one or more anti-tack agents. In someembodiments, the drug coating comprises amantadine, or apharmaceutically acceptable salt thereof; at least two pharmaceuticallyacceptable excipients; and one or more anti-tack agents. In someembodiments, the one or more, or at least two, pharmaceuticallyacceptable excipients comprise one or more binders. In some embodiments,the one or more, or at least two pharmaceutically acceptable excipientsare binders. In a certain embodiment, the drug coating comprisesamantadine, or a pharmaceutically acceptable salt thereof; one or morebinders; and one or more anti-tack agents. In some embodiments, thepharmaceutically acceptable salt of amantadine is amantadinehydrochloride. In another embodiment, the pharmaceutically acceptablesalt of amantadine is amantadine sulfate.

In some embodiments, the drug coating comprises from 60 wt % to 85 wt %,from 65 wt % to 80 wt %, or from 70 wt % to 75 wt % of apharmaceutically acceptable salt of amantadine; from 15 wt % to 35 wt %,or from 20 wt % to 30 wt % of one or more binders; and from 1 wt % to 5wt %, or from 2 wt % to 4 wt % of one or more anti-tack agents. In someembodiments, the pharmaceutically acceptable salt of amantadine isamantadine hydrochloride; the one or more binders are hydroxypropylmethyl cellulose and copovidone; and the one or more anti-tack agentsare talc. In some embodiments, the drug coating comprises amantadine, ora pharmaceutically acceptable salt thereof; hydroxypropyl methylcellulose; copovidone; and talc. In some embodiments, the drug coatingcomprises from 60 wt % to 85 wt %, from 65 wt % to 80 wt %, or from 70wt % to 75 wt % of a pharmaceutically acceptable salt of amantadine;from 15 wt % to 25 wt %, or from 18 wt % to 22 wt % ofhydroxypropylmethyl cellulose; from 2 wt % to 7 wt %, or from 3 wt % to6 wt % of copovidone; and from 1 wt % to 5 wt %, or from 2 wt % to 4 wt% of talc.

In certain embodiments, the drug coating comprises less than 6000 ppm,less than 5500 ppm, less than 5000 ppm, less than 4500 ppm, less than4000 ppm, less than 3500 ppm, less than 3000 ppm, less than 2500 ppm,less than 2000 ppm, less than 1500 ppm, or less than 1200 ppm organicsolvent. In certain embodiments, the organic solvent is alcohol, forexample isopropyl alcohol. In some embodiments, the organic solvent is alinear or cyclic ketone (e.g., acetone, methyl ethyl ketone, etc.) Insome embodiments, the organic solvent is a sulfoxide (e.g., dimethylsulfoxide, etc). In some embodiments, the organic solvent is an amide(e.g., dimethyl formamide, N-methyl pyrrolidone, hexamethyl phosphoroustriamide (HMPT), etc.). In some embodiments, the organic solvent is alinear or cyclic ether (e.g., tetrahydrofuran, diethyl ether,bis(2-methoxyethyl) ether (diglyme), dimethoxy ethane (glyme),1,4-dioxane, etc.). In some embodiments, the organic solvent is aphosphoramide (e.g., hexamethyl phosphoramide (HPMA), etc.). In someembodiments, the organic solvent is a chlorinated hydrocarbon (e.g.,chloroform, dichloromethane, dichloro ethane, carbon tetrachloride,etc.). In some embodiments, the organic solvent is a glycol (e.g.,ethylene glycol, diethylene glycol, propylene glycol, etc.). In someembodiments, the organic solvent is a, nitrogen-containing solvent(e.g., pyridine, acetonitrile, etc.). In some embodiments, the organicsolvent is an alcohol (e.g., a C₁-C₆ alcohol (e.g., ethanol, methanol,isopropanol, 1-butanol, 2-butanol, glycerol), such as isopropyl alcohol.In some embodiments, mixtures of two or more solvents can be used. Insome embodiments of the levels of organic solvent described herein, theprovided level refers to the total amount of two or more organicsolvents.

In some embodiments, the core seeds are coated with a drug coatcomprising amantadine or a pharmaceutically acceptable salt thereof, andoptionally one or more binders, anti-tack agents and/or solvents byconventional coating techniques such as fluidized bed coating, pancoating. In some embodiments, the solvents exclude organic solvents. Inother embodiments, the solvent for the drug coating composition consistsof water.

B. Extended Release Coating

The coated core seeds further comprise an extended release coating,wherein the extended release coating surround the drug coating. Theextended release coating may be formulated to delay release of the drugfrom the coated core seeds for a period of time after introduction ofthe dosage form into the use environment. The extended release coatingcomprises one or more release modifying excipients. For example, theextended release coating may comprise one or more pH-dependent ornon-pH-dependent release modifying excipients, or a combination thereof.Examples of non-pH-dependent extended release polymers include ethylcellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, carboxymethyl cellulose, copolymer of ethylacrylate, and methyl methacrylate (e.g., Eudragit RS). Examples ofpH-dependent release modifying excipients include methacrylic acidcopolymers, hydroxypropylmethyl cellulose acetate succinate,hydroxypropylmethyl cellulose phthalate, and cellulose acetatephthalate. The extended release coating may further comprise one or morepore-forming agents. Example of pore-forming agents include povidone;polyethylene glycol; hydroxypropyl cellulose; hydroxypropylmethylcellulose; sugars, such as sucrose, mannitol, and lactose; and salts,such as sodium chloride and sodium citrate. The extended release coatingmay further comprise one or more plasticizers, such as acetylatedcitrated esters, acetylated glycerides, castor oil, citrate esters,dibutylsebacate, glyceryl monostearate, diethyl phthalate, glycerol,medium chain triglycerides, propylene glycol, or polyethylene glycol.The extended release coating may also include one or more additionalexcipients, for example one or more lubricants, one or more anti-tackagents. For example, in some embodiments, the extended release coatingcomprises one or more excipients selected from the group consisting ofmagnesium stearate, calcium silicate, magnesium silicate, colloidalsilicon dioxide and talc. In some embodiments, the extended releasecoating comprises one or more lubricants such as magnesium stearate ortalc.

As described herein, the extended release coating comprising one or morerelease modifying excipients. Release modifying excipients may include,but are not limited to, insoluble plastics, hydrophilic polymers, andfatty compounds. Plastic matrices include, but are not limited to,methyl acrylate-methyl methacrylate, polyvinyl chloride, andpolyethylene. Hydrophilic polymers include, but are not limited to,cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, and cross-linked acrylic acidpolymers like Carbopol® 934, polyethylene oxides and mixtures thereof.Fatty compounds include, but are not limited to, various waxes such ascarnauba wax and glyceryl tristearate and wax-type substances includinghydrogenated castor oil or hydrogenated vegetable oil, or mixturesthereof. In certain embodiments, the plastic material is apharmaceutically acceptable acrylic polymer, including but not limitedto, acrylic acid and methacrylic acid copolymers, methyl methacrylate,methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymerpoly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In certain other embodiments, theacrylic polymer is comprised of one or more ammonio methacrylatecopolymers. Ammonio methacrylate copolymers are well known in the art,and are described in NF XVII as fully polymerized copolymers of acrylicand methacrylic acid esters with a low content of quaternary ammoniumgroups. In still other embodiments, the acrylic polymer is an acrylicresin lacquer such as that which is commercially available from RohmPharma under the trade name Eudragit®. In further embodiments, theacrylic polymer comprises a mixture of two acrylic resin lacquerscommercially available from Rohm Pharma under the trade names Eudragit®RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit®RS30D are copolymers of acrylic and methacrylic esters with a lowcontent of quaternary ammonium groups, the molar ratio of ammoniumgroups to the remaining neutral (meth)acrylic esters being 1:20 inEudragit RL30D and 1:40 in Eudragit® RS30D. The mean molecular weight isabout 150,000. Eudragit® S-100 and Eudragit® L-100 are also suitable foruse herein. The code designations RL (high permeability) and RS (lowpermeability) refer to the permeability properties of these agents.Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids.However, multiparticulate systems formed to include the same areswellable and permeable in aqueous solutions and digestive fluids. Thepolymers described above such as Eudragit® RL/RS may be mixed togetherin any desired ratio in order to ultimately obtain an extended releaseformulation having a desirable dissolution profile. One skilled in theart will recognize that other acrylic polymers may also be used, suchas, for example, Eudragit® L.

As described herein, in some embodiments the extended release coatingcomprises one or more pore-forming agents (e.g., pore formers).Pore-forming agents suitable for use in the extended release coating canbe organic or inorganic agents, and may include materials that can bedissolved, extracted or leached from the coating in the environment ofuse. Examples of pore-forming agents include but are not limited toorganic compounds such as mono-, oligo-, and polysaccharides includingsucrose, glucose, fructose, mannitol, mannose, galactose, lactose,sorbitol, pullulan, dextran; polymers soluble in the environment of usesuch as water-soluble hydrophilic polymers, such as povidone,crospovidone, polyethylene glycol, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxyalkyl celluloses, carboxyalkylcelluloses, cellulose ethers, acrylic resins, polyvinylpyrrolidone,cross-linked polyvinylpyrrolidone, polyethylene oxide, carbowaxes,Carbopol®, and the like, diols, polyols, polyhydric alcohols,polyalkylene glycols, polyethylene glycols, polypropylene glycols, orblock polymers thereof, polyglycols, poly(α-Ω) alkylenediols; inorganiccompounds such as alkali metal salts, lithium carbonate, sodiumchloride, sodium bromide, potassium chloride, potassium sulfate,potassium phosphate, sodium acetate, sodium citrate, suitable calciumsalts, and the like. In certain embodiments, plasticizers can also beused as a pore forming agent. In some embodiments, the release modifyingexcipient is ethyl cellulose. In certain embodiments, the pore formingagent is povidone, HPMC, or Eudragit®, or any combinations thereof.

In some embodiments, the extended release coating comprises one or morerelease modifying excipients; one or more pore forming agents, and oneor more plasticizers. In some embodiments, the extended release coatingcomprises between 65 wt % to 95 wt %, or between 70 wt % to 90 wt %, orbetween 75 wt % to 85 wt % of one or more release modifying excipients;between 5 wt % to 15 wt %, or between 8 wt % to 12 wt % of one or morepore forming agents; and between 5 wt % to 15 wt %, or between 8 wt % to12 wt % of one or more plasticizers. In some embodiments, the one ormore release modifying excipients is ethyl cellulose; the one or morepore forming agents is povidone, HPMC, or Eudragit®, or a mixturethereof, and the one or more plasticizers is medium chain triglycerides.Thus, in some embodiments, the extended release coating comprisesbetween 65 wt % to 95 wt %, or between 70 wt % to 90 wt %, or between 75wt % to 85 wt % of ethyl cellulose; between 5 wt % to 15 wt %, orbetween 8 wt % to 12 wt % of povidone; and between 5 wt % to 15 wt %, orbetween 8 wt % to 12 wt % of medium chain triglycerides.

In certain embodiments, the extended release coating comprises less than6000 ppm, less than 5500 ppm, less than 5000 ppm, less than 4500 ppm,less than 4000 ppm, less than 3500 ppm, less than 3000 ppm, less than2500 ppm, less than 2000 ppm, less than 1500 ppm, or less than 1200 ppmorganic solvent. In certain embodiments, the organic solvent is alcohol,for example isopropyl alcohol. In some embodiments, the organic solventis a linear or cyclic ketone (e.g., acetone, methyl ethyl ketone, etc.)In some embodiments, the organic solvent is a sulfoxide (e.g., dimethylsulfoxide, etc). In some embodiments, the organic solvent is an amide(e.g., dimethyl formamide, N-methyl pyrrolidone, hexamethyl phosphoroustriamide (HMPT), etc.). In some embodiments, the organic solvent is alinear or cyclic ether (e.g., tetrahydrofuran, diethyl ether,bis(2-methoxyethyl) ether (diglyme), dimethoxy ethane (glyme),1,4-dioxane, etc.). In some embodiments, the organic solvent is aphosphoramide (e.g., hexamethyl phosphoramide (HPMA), etc.). In someembodiments, the organic solvent is a chlorinated hydrocarbon (e.g.,chloroform, dichloromethane, dichloro ethane, carbon tetrachloride,etc.). In some embodiments, the organic solvent is a glycol (e.g.,ethylene glycol, diethylene glycol, propylene glycol, etc.). In someembodiments, the organic solvent is a, nitrogen-containing solvent(e.g., pyridine, acetonitrile, etc.). In some embodiments, the organicsolvent is an alcohol (e.g., a C₁-C₆ alcohol (e.g., ethanol, methanol,isopropanol, 1-butanol, 2-butanol, glycerol), such as isopropyl alcohol.In some embodiments, mixtures of two or more solvents can be used. Insome embodiments of the levels of organic solvent described herein, theprovided level refers to the total amount of two or more organicsolvents.

Extended release coating can be applied using conventional coatingtechniques such as fluidized bed coating, pan coating etc. The drugcoated core seeds, which optionally comprise a seal coat, may be coatedwith the extended release coating by fluidized bed coating.

C. Additional Coatings

In some embodiments, the coated core seeds comprise one or moreadditional coatings, for example a seal coat. In some embodiments, theseal coat is formulated to prevent one or more components of theextended release coating from interacting with one or more components ofthe core seed, or to prevent migration of one or more components of thecore seed and/or drug coating from diffusing into the extended releasecoating. The seal coating may comprise one or more film forming polymersincluding but not limited to hydroxypropylmethyl cellulose (HPMC),copovidone, povidone, polyvinyl pyrrolidone, hydroxypropyl cellulose,hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose or anycombinations thereof, and the like.

The seal coating may further comprise one or more additionalpharmaceutically acceptable excipients. For example, the seal coatingmay comprise one or more plasticizers, such as propylene glycol,triacetin, polyethylene glycol, or tributyl citrate, or any combinationthereof; or one or more anti-tack agents, such as magnesium stearate,calcium silicate, magnesium silicate, colloidal silicon dioxide or talc,or any combinations thereof. In some embodiments, the film formingpolymer is HPMC, copovidone, povidone, or a combination thereof. In someembodiments, the film forming polymer is HPMC.

The seal coating may further comprise one or more buffers, colorants,opacifiers, surfactants or bases, which are known to those skilled inthe art.

In certain embodiments, the seal coating comprises one or more filmforming polymers and one or more anti-tack agents. In some embodiments,the seal coating comprises from 80 wt % to 100 wt %, or from 85 wt % to95 wt % of one or more film forming polymers; and from 0 wt % to 20 wt%, or from 5 wt % to 15 wt % or from 7 wt % to 13 wt % of one or moreanti-tack agents. In certain embodiments, the seal coating compriseshydroxpropyl methyl cellulose and talc. In some embodiments, the sealcoating comprises from 80 wt % to 100 wt %, or from 85 wt % to 95 wt %hydroxypropyl methyl cellulose; and from 0 wt % to 20 wt %, or from 5 wt% to 15 wt % or from 7 wt % to 13 wt % talc.

In certain embodiments, the seal coating comprises less than 6000 ppm,less than 5500 ppm, less than 5000 ppm, less than 4500 ppm, less than4000 ppm, less than 3500 ppm, less than 3000 ppm, less than 2500 ppm,less than 2000 ppm, less than 1500 ppm, or less than 1200 ppm organicsolvent. In certain embodiments, the organic solvent is alcohol, forexample isopropyl alcohol. In some embodiments, the organic solvent is alinear or cyclic ketone (e.g., acetone, methyl ethyl ketone, etc.) Insome embodiments, the organic solvent is a sulfoxide (e.g., dimethylsulfoxide, etc.). In some embodiments, the organic solvent is an amide(e.g., dimethyl formamide, N-methyl pyrrolidone, hexamethyl phosphoroustriamide (HMPT), etc.). In some embodiments, the organic solvent is alinear or cyclic ether (e.g., tetrahydrofuran, diethyl ether,bis(2-methoxyethyl) ether (diglyme), dimethoxy ethane (glyme),1,4-dioxane, etc.). In some embodiments, the organic solvent is aphosphoramide (e.g., hexamethyl phosphoramide (HPMA), etc.). In someembodiments, the organic solvent is a chlorinated hydrocarbon (e.g.,chloroform, dichloromethane, dichloroethane, carbon tetrachloride,etc.). In some embodiments, the organic solvent is a glycol (e.g.,ethylene glycol, diethylene glycol, propylene glycol, etc.). In someembodiments, the organic solvent is a, nitrogen-containing solvent(e.g., pyridine, acetonitrile, etc.). In some embodiments, the organicsolvent is an alcohol (e.g., a C₁-C₆ alcohol (e.g., ethanol, methanol,isopropanol, 1-butanol, 2-butanol, glycerol)), such as isopropylalcohol. In some embodiments, mixtures of two or more solvents can beused. In some embodiments of the levels of organic solvent describedherein, the provided level refers to the total amount of two or moreorganic solvents.

Seal coating can be applied to the core seeds using conventional coatingtechniques such as fluidized bed coating, pan coating etc. In someembodiments, the drug coated core seeds are coated with a seal coatcoating that optionally comprises one or more binders, anti-tack agentsand/or solvents by fluidized bed coating or pan coating. In certainembodiments, the solvents exclude organic solvents. In some embodiments,the solvent for the seal coating composition consists of water.

D. Binders

In some embodiments, the drug coating, or the additional coating, ifpresent, or any combinations thereof, comprise one or more binders(e.g., film forming polymers). For example, as described herein the drugcoating comprises one or more pharmaceutically acceptable excipients,wherein the one or more pharmaceutically acceptable excipients maycomprise a binder. Suitable binders for use herein may include alginicacid and salts thereof; cellulose derivatives such ascarboxymethylcellulose, methylcellulose (e.g., Methocel®),hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®),and microcrystalline cellulose (e.g., Avicel®); microcrystallinedextrose; amylose; magnesium aluminum silicate; polysaccharide acids;bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer;crospovidone; povidone; starch; pregelatinized starch; dextrin; a sugar,such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol,sorbitol, xylitol (e.g., Xylitab®), and lactose; a natural or syntheticgum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

E. Capsules

In some embodiments, the oral pharmaceutical compositions herein furthercomprise a capsule shell, wherein the plurality of coated core seeds isencapsulated within the capsule shell. The coated core seeds may beintroduced into a suitable capsule shell by using an encapsulatorequipped with pellet dosing chamber. The capsule sizes may be 00, 0,0EL, 1, 1EL, 2, 2EL, 3, 4 or 5. In some embodiments, a unit dose of anoral pharmaceutical composition is encapsulated within one capsuleshell. In other variations, a unit dose of an oral pharmaceuticalcomposition as described herein is encapsulated within a plurality ofseparate capsule shells, for example split between two capsule shells.

In some embodiments, the composition that provides pharmacokineticproperties and plasma concentration profiles is a pellet-in-capsulecomposition wherein the pellets are a plurality of coated core seedsthat have a diameter of about 500 μm to 1.2 mm, and preferably about 700μm to 1000 μm, where each coated core seed comprises a core seed; a drugcoating surrounding the core seed and comprising amantadine or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient; and an extended release coating surrounding thedrug coating, and comprising a release modifying excipient. In someembodiments, the extended release coating extends release of theamantadine or a pharmaceutically acceptable salt thereof so as toprovide the desired pharmacokinetic properties and amantadine plasmaconcentration profiles described herein.

In some embodiments, the plurality of coated core seeds in thepellet-in-capsule formulation are in a size 0 or smaller, preferably asize 1 or smaller capsule. Mean coated core seed diameters in someembodiments may be in a range of 500 μm to 1200 μm, e.g., from 500 μm to1100 μm, from 500 μm to 1000 μm, from 500 μm to 900 μm, from 500 μm to800 μm, from 500 μm to 700 μm, from 600 μm to 1100 μm, from 600 μm to1000 μm, from 600 μm to 900 μm, from 600 μm to 800 μm, from 600 μm to700 μm, from 700 μm to 1100 μm, from 700 μm to 1000 μm, from 700 μm to900 μm, or from 700 μm to 800 μm. In some embodiments the mean particlediameters are, ±10%, e.g.: 500 μm, 550 μm, 600 μm, 650 μm, 700 μm, 750μm, 800 μm, 850 μm, 900 μm, 950 μm, 1000 μm, 1050 μm, 1100 μm, 1150 μmor 1200 μm.

In some embodiments, the composition of the disclosure is an oralpharmaceutical composition, comprising a plurality of coated core seedsencapsulated within a capsule shell, wherein each coated core seedcomprises a core seed; a drug coating amantadine, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptableexcipients, wherein the one or more pharmaceutically acceptableexcipients is one or more binders, and wherein the drug coatingsurrounds the core seed; and an extended release coating surrounding thedrug coating, wherein the extended release coating comprising a releasemodifying excipient (such as ethyl cellulose), a pore forming agent(such as hydroxypropyl methyl cellulose or povidone), and a plasticizer.In some embodiments, the coated core seeds may further comprise a sealcoating surrounding the drug coating, wherein the extended releasecoating surrounds the seal coating. The coated core seeds may beprepared using methods known in the art, such as those described inExample 2 below.

In a specific embodiment, based on the combined weight of the pluralityof coated core seeds, amantadine or a pharmaceutically acceptable saltthereof is present in amounts from 20-80 wt %, 45-70 wt %, 40-50 wt %,45-55 wt %, 50-60 wt %, 55-65 wt %, 60-70 wt %, 65-75 wt %, 70-80 wt %,or 40 to 60 wt %; the one or more pharmaceutically acceptable excipients(such as one or more binders, for example hydroxypropyl methylcellulose, copovidone, or mixtures thereof) is present in amounts from 1to 25 wt %; the core seed, for example a sugar sphere (nonpareil) ormicrocrystalline cellulose seed (e.g., Celphere®), is present in amountsfrom 8 to 25 wt %; the extended release coating comprises one or morerelease modifying excipients, one or more pore forming agents, and oneor more plasticizers, wherein the release modifying excipient comprisesethyl cellulose present in amounts from 10 to 20 wt %, the pore formingagent, preferably povidone, is present in amounts from 1 to 4 wt %, andthe plasticizer is present in amounts from 1 to 4 wt %. In anotherspecific embodiment, based on the combined weight of the plurality ofcoated core seeds, the amantadine or pharmaceutically acceptable saltthereof is present in amounts from 50 to 70 wt %; the one or morepharmaceutically acceptable excipients (such as one or more binders, forexample hydroxypropyl methyl cellulose, copovidone, or mixtures thereof)is present in amounts from 1 to 25 wt %; the core seed, for example asugar sphere (nonpareil) or microcrystalline cellulose seed (e.g.,Celphere®), is present in amounts from 5 to 15 wt %; the one or morerelease modifying excipients in the extended release coating is ethylcellulose and is present in amounts from 1 to 15 wt %; the extendedrelease coating comprises pore forming agent (such as povidone) which ispresent in amounts from 0.25 to 4 wt %; and the extended release coatingcomprises a plasticizer, which is present in amounts from 0.25 to 4 wt%.

In some embodiments, provided herein is an oral pharmaceuticalcomposition, comprising a plurality of coated core seeds and at leastone capsule shell, wherein at least a portion of the core seeds areencapsulated within the capsule shell. In some embodiments, theplurality of the coated core seeds are encapsulated in two separatecapsule shells. In some embodiments, the plurality of coated core seedscomprise core seeds, wherein the core seeds comprise microcrystallinecellulose from 5 wt % to 20 wt %, or from 10 wt % to 15 wt %, or about12.44 wt % of the composition. In some embodiments, the coated coreseeds comprise a drug coating surrounding each core seed, wherein thedrug coating comprises amantadine, or a pharmaceutically acceptable saltthereof from 20 wt % to 60 wt %, or from 30 wt % to 50 wt %, or from 40wt % to 50 wt %, or about 43.54 wt % of the composition; thepharmaceutically acceptable excipients hydroxypropyl methyl cellulosefrom 5 wt % to 18 wt %, or from 8 wt % to 15 wt %, or about 11.61 wt %,and copovidone at from 1 wt % to 5 wt %, or from 2 wt % to 4 wt %, orabout 2.9 wt % of the composition; and the anti-tack agent talc at from1 wt % to 3 wt %, or from 1.5 wt % to 2.5 wt %, or about 2.17 wt % ofthe composition. In certain embodiment, the amantadine or a salt thereofis amantadine hydrochloride. In other embodiments, the coated core seedscomprise an extended release coating surrounding the drug coating,wherein the extended release coating comprises the release modifyingexcipient ethyl cellulose from 5 wt % to 25 wt %, or 10 wt % to 20 wt %,or about 15.91 wt % of the composition; the pore forming agent povidoneat from 1 wt % to 3 wt %, or from 1.5 wt % go 2.5 wt %, or about 2.15 wt% of the composition; and the plasticizer medium chain triglyceridesfrom 1 wt % to 3 wt %, or from 1.5 wt % go 2.5 wt %, or about 2.15 wt %of the composition. In certain embodiments, which may be combined withany of the previous embodiments, the coated core seeds comprise a sealcoating surrounding the drug coating, wherein the extended releasecoating surrounds the seal coating, and the seal coating comprises thefilm-forming polymer hydroxpropyl methyl cellulose from 3 wt % to 10 wt%, or 5 wt % to 8 wt %, or about 6.6 wt % of the composition; and theanti-tack agent talc at from 0.25 wt % to 1 wt %, or from 0.5 wt % to0.75 wt %, or about 0.66 wt % of the composition. In certainembodiments, the pharmaceutical composition further comprises magnesiumstearate from 0.01 wt % to 0.2 wt %, or 0.08 wt % to 0.12 wt %, or about0.1 wt % of the composition.

In some embodiments, the pharmaceutically acceptable salt of amantadineis amantadine hydrochloride. In another embodiment, the pharmaceuticallyacceptable salt of amantadine is amantadine sulfate. In someembodiments, which may be combined with any other embodiments, the oralpharmaceutical composition comprises amantadine in a unit dosage from 40mg to 500 mg, 45 mg to 400 mg, from 50 mg to 350 mg, from 55 mg to 300mg, from 60 mg to 290 mg, from 68.5 mg to 274 mg, from 50 mg to 80 mg,from 55 mg to 75 mg, from 60 mg to 70 mg, from 120 mg to 150 mg, from135 mg to 145 mg, from 130 mg to 140 mg, from 250 mg to 300 mg, from 260mg to 290 mg, from 270 mg to 280 mg, about 68.5 mg, about 137 mg, orabout 274 mg, or comprises an equivalent amount of a pharmaceuticallyacceptable salt of amantadine. In some embodiments, the pharmaceuticallyacceptable salt of amantadine is amantadine hydrochloride. In anotherembodiment, the pharmaceutically acceptable salt of amantadine isamantadine sulfate. It should be clear to one of skill in the art how tocalculate an “equivalent amount” of the salt of a compound, taking intoaccount that the salt has an increased molecular weight. For example, insome embodiments, the composition comprises about 68.5 mg of amantadine,or an equivalent amount of the amantadine hydrochloride salt. Thus, insome embodiments, the composition comprises about 85 mg of amantadinehydrochloride. The unit dosage may be in a single capsule, or it may beacross multiple capsules.

As described herein, in some embodiments, the pharmaceutical compositionhas a lower level of organic solvent than other compositions. In someembodiments, the pharmaceutical composition comprise a plurality ofcoated core seeds, wherein the plurality of coated core seeds has alower level or organic solvent than other compositions. For example, insome embodiments, the pharmaceutical compositions provided herein, suchas any of the embodiments disclosed herein, comprise a plurality ofcoated core seeds with less than 6000 ppm, less than 5500 ppm, less than5000 ppm, less than 4500 ppm, less than 4000 ppm, less than 3500 ppm,less than 3000 ppm, less than 2500 ppm, less than 2000 ppm, less than1500 ppm, or less than 1200 ppm organic solvent. In some embodiments,the pharmaceutical composition as described herein comprises less than6000 ppm, less than 5500 ppm, less than 5000 ppm, less than 4500 ppm,less than 4000 ppm, less than 3500 ppm, less than 3000 ppm, less than2500 ppm, less than 2000 ppm, less than 1500 ppm, or less than 1200 ppmorganic solvent. In certain embodiments the organic solvent is alcohol.In some embodiments, the organic solvent is isopropyl alcohol. In otherembodiments, the organic solvent comprises one or more compounds. Forexample, in some embodiments, the organic solvent comprises isopropylalcohol and another alcohol. In some embodiments, the organic solvent isa linear or cyclic ketone (e.g., acetone, methyl ethyl ketone, etc.) Insome embodiments, the organic solvent is a sulfoxide (e.g., dimethylsulfoxide, etc.). In some embodiments, the organic solvent is an amide(e.g., dimethyl formamide, N-methyl pyrrolidone, hexamethyl phosphoroustriamide (HMPT), etc.). In some embodiments, the organic solvent is alinear or cyclic ether (e.g., tetrahydrofuran, diethyl ether,bis(2-methoxyethyl) ether (diglyme), dimethoxy ethane (glyme),1,4-dioxane, etc.). In some embodiments, the organic solvent is aphosphoramide (e.g., hexamethyl phosphoramide (HPMA), etc.). In someembodiments, the organic solvent is a chlorinated hydrocarbon (e.g.,chloroform, dichloromethane, dichloroethane, carbon tetrachloride,etc.). In some embodiments, the organic solvent is a glycol (e.g.,ethylene glycol, diethylene glycol, propylene glycol, etc.). In someembodiments, the organic solvent is a, nitrogen-containing solvent(e.g., pyridine, acetonitrile, etc.). In some embodiments, the organicsolvent is an alcohol (e.g., a C₁-C₆ alcohol (e.g., ethanol, methanol,isopropanol, 1-butanol, 2-butanol, glycerol)), such as isopropylalcohol. In some embodiments, mixtures of two or more solvents can beused. In some embodiments of the levels of organic solvent describedherein, the provided level refers to the total amount of two or moreorganic solvents.

Additional embodiments of the disclosure are illustrated in the Table A,below, entitled “Various Amantadine ER Capsule Size 1 Formulations”. Bymeans of methods and compositions described herein, formulations can bemade that achieve the desired dissolution characteristics and targetpharmacokinetic profiles described herein. More specifically,therapeutically effective doses of amantadine or a pharmaceuticallyacceptable salt thereof can be administered once nightly in no more thantwo size 1 (or smaller, e.g., size 2 or 3) capsules using themanufacturing methods and compositions that have been described hereinto achieve these results. In particular, higher drug loading can beachieved using compositions and manufacturing methods described herein.In some embodiments, higher drug loading may be achieved, with therequired dissolution profile, using smaller coated core seed sizes andconcomitantly increased thickness of the drug coating or multiple drugcoatings on smaller core seeds, but with no change in the extendedrelease coat. In some embodiments, using alternative manufacturingapproaches described herein, e.g., extrusion and spheronization, evenhigher drug loads can be achieved to realize the desired dissolutionprofile, enabling high amantadine drug loads with suitablepharmacokinetic profiles, resulting in compositions that aretherapeutically more effective, and at least as well tolerated, and canbe filled in relatively small sized capsules (e.g., size 1, 2 or 3),enabling ease of administration to subjects.

TABLE A Various Amantadine ER Capsule Size 1 Formulations Extended AMT*Inert Core Active Release Bulk % Fill in Strength Manufacture PelletSize Drug Coating Density Size 1 (mg) Method (mm) % w/w % w/w (g/cm³)Capsule  85 mg Fluid bed 0.3-0.5 40-50% 10-30% 0.6-1.0 60-70% coating110 mg Fluid bed 0.3-0.5 40-50% 10-30% 0.6-1.0 60-70% coating 140 mgFluid bed 0.3-0.5 45-50% 10-30% 0.6-1.0 80-90% coating 150 mg Fluid bed0.3-0.5 50-55% 10-30% 0.6-1.0 80-90% coating 170 mg Fluid bed 0.2-0.350-55% 10-30% 0.6-1.0 80-90% coating 170 mg Extrusion N/A 55-75% 10-30%0.6-1.0 65-75% spheronization, pan or fluidized bed coating 190 mgExtrusion N/A 55-75% 10-30% 0.6-1.0 75-85% spheronization, pan orfluidized bed coating 210 mg Extrusion N/A 55-75% 10-30% 0.6-1.0 80-90%spheronization, pan or fluidized bed coating 230 mg Extrusion N/A 55-75%10-30% 0.6-1.0 85-95% spheronization, pan or fluidized bed coating*“AMT” refers to amantadine hydrochloride

Suitable plasticizers include medium chain triglycerides, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, castor oil, and the like. The coated core seeds are filledinto capsules to provide the desired strength of amantadine. Anadvantage of this composition is it provides the desired releaseproperties that make the composition suitable for administration duringsaid period before bedtime. A further advantage is that the extendedrelease coating is sufficiently durable so that the capsule can beopened and the pellets sprinkled onto food for administration tosubjects who have difficulty swallowing pills, without adverselyaffecting the release properties of the composition. When thecomposition is administered by sprinkling onto food, it is preferred touse a soft food such as applesauce or chocolate pudding, which isconsumed within 30 minutes, and preferably within 15 minutes. In someembodiments, a yet further advantage of the composition described hereinis that it has very good batch-to-batch reproducibility and shelf-lifestability.

In some embodiments of the pellet-in-capsule composition of thedisclosure, in addition to having the in vitro dissolution propertiesdescribed herein and any of the pharmacokinetic properties providedherein (e.g., in vivo release profile, Tmax, Cmax/Cmin ratio, etc) thatmake the composition suitable for administration in said period beforebedtime. The composition is further characterized by providing a Cmax of1.3-2.4 ng/ml per mg of amantadine and an AUC_(0-inf) of 42-75 ng*h/mLper mg of amantadine after oral administration of a single dose of thecapsule to a human subject in a fasted state. In some embodiments, thepellet-in-capsule composition is further characterized by a steady stateplasma concentration in which once nightly oral administration of thecapsule to a human subject provides a Cmax of 2.4 to 4.2 ng/ml per mg ofamantadine, a Cmin of 1.1 to 2.6 ng/ml per mg of amantadine, and anAUC₀₋₂₄ of 43-73 ng*h/mL per mg of amantadine.

The pellet-in-capsule compositions provided herein may be provided at astrength suitable for amantadine therapy. Typical strengths range fromat least about 50 mg to about 250 mg. In a specific embodiment, thecapsule strength of amantadine is 70 mg, 80 mg, 85 mg, 90 mg, 110 mg,120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 160 mg, 170 mg, 180 mg,190 mg, 210 mg, or 220 mg, or an equivalent amount of a pharmaceuticallyacceptable salt thereof, that provides a single dose AUC_(0-inf) per mgthat is equivalent to a 100 mg tablet of an immediate releaseformulation of amantadine HCl (e.g., Symmetrel®, or other FDA OrangeBook reference listed drug). In some embodiments, the capsule strengthis 68.5 mg, 70 mg, 80 mg, 85 mg, 90 mg, 110 mg, 120 mg, 125 mg, 130 mg,137 mg, 140 mg, 150 mg, 160 mg, 160 mg, 170 mg, 180 mg, 190 mg, 205.5mg, 210 mg, or 220 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof, that provides a single doseAUC_(0-inf) per mg that is equivalent to a 100 mg tablet of an immediaterelease formulation of amantadine HCl (e.g., Symmetrel®, or other FDAOrange Book reference listed drug). For example, in some embodiments,the capsule strength comprises 85 mg of amantadine hydrochloride or 170mg of amantadine hydrochloride. One, two, or three, of such capsules canbe administered to a subject in the period before bedtime. In someembodiments, between 220 mg and 650 mg of amantadine hydrochloride isadministered using 2 capsules of a suitable ER formulations oncenightly. In still further embodiments, the capsule strength is fromabout 60 mg to about 155 mg, about 60 mg to about 80 mg, or about 120 mgto about 155 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof. In certain embodiments, thecapsule strength is from about 75 mg to about 190 mg, about 75 mg toabout 95 mg, or about 150 mg to about 190 mg of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof. One,two, or three, of such capsules can be administered to a subject in theperiod before bedtime.

III. Methods of Preparing

Also provided herein are methods of preparing the pharmaceuticalcompositions described herein. As discussed herein, in some embodiments,certain steps of the methods do not include an organic solvent. Avoidingthe use of organic solvent in certain steps of the preparation mayresult in pharmaceutical compositions with a lower residual organicsolvent level, and lower incidence of one or more gastrointestinaleffects when administered to a subject. In some embodiments, thegastrointestinal effects are selected from the group consisting ofabdominal distension, constipation, diarrhea, dyspepsia, gingival pain,dry lip, lower abdominal pain, nausea, stomach discomfort, toothache,upper abdominal pain, and vomiting.

As described herein, in some embodiments, the pharmaceuticalcompositions provided herein comprise a plurality of coated core seedscomprising core seeds and one or more coatings surrounding the coreseeds, such as a drug coating, extended release coating, or sealcoating, or mixtures thereof. These coatings may be applied, forexample, by combining one or more of the coating components with asolvent to form a coating mixture, and applying the coating mixture tothe core seeds through, for example, spraying the coating mixture on thecore seeds. This may be done, for example, in a fluidized bed. Thesprayed core seeds may then optionally be dried, and an additionalcoating be applying (for example, a drug coating followed by an extendedrelease coating). The process parameters for applying a coating to aplurality of core seeds, such as temperature air speed, inlet airtemperature, spray rate, drying time, nozzle configuration, and otherswould be understood by a person of skill in the art.

In some embodiments, the coated core seeds comprise a drug coatingsurrounding the core seeds. This drug coating may be prepared bycombining one or more drug coating components (e.g., amantadine or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients) with a solvent to produce a drugmixture, and coating a plurality of core seeds with the drug mixture. Insome embodiments, using a solvent that is not an organic solvent, orthat comprises, e.g., less than 1 wt % organic solvent, may result in apharmaceutical composition with a lower level of residual organicsolvent. Similarly, the seal coating, if present, may be preparedcombining one or more seal coating components (such as a film-coatingpolymer) with a solvent to produce a seal coat mixture, and coating aplurality of core seeds with the seal coat mixture. In some embodiments,using a solvent that is not an organic solvent, or that comprises, e.g.,less than 1 wt % organic solvent, may result in a pharmaceuticalcomposition with a lower level of residual organic solvent. As discussedherein, reducing the level of organic solvent in the pharmaceuticalcomposition compared to a composition prepared with organic solvents inthe drug coating and/or seal coating steps may result in reducedgastrointestinal effects in a subject. In certain embodiments, one ormore of the components is a suspension when combined with the solvent.For, example, in certain embodiments, the release modifying excipient isprepared as a suspension in water, then combined with other componentsand a solvent to produce the extended release coating mixture.

Thus, in some aspects, provided herein is a process of preparing an oralpharmaceutical composition comprising amantadine, or a pharmaceuticallyacceptable salt thereof, comprising:

-   -   a) coating a plurality of core seeds with a drug mixture to form        a plurality of drug-coated core seeds; wherein the drug mixture        comprises amantadine or a pharmaceutically acceptable salt        thereof, one or more pharmaceutically acceptable excipients, and        solvent; and wherein the drug mixture comprises less than 1 wt %        organic solvent;    -   b) coating the plurality of drug-coated core seeds with an        extended release mixture to form extended-release coated core        seeds; wherein the extended release mixture comprises one or        more release modifying excipients and solvent;    -   c) drying the plurality of extended release-coated core seeds;        and    -   d) encapsulating the plurality of extended release-coated core        seeds in a capsule shell to produce the oral pharmaceutical        composition; wherein the oral pharmaceutical composition        comprises a core seed, a drug coating layer comprising        amantadine, or a pharmaceutically acceptable salt thereof, an        extended release coating layer;    -   and wherein the plurality of extended release-coated core seeds        comprises less than 6000 ppm organic solvent.

In some embodiments, the process further comprises coating the pluralityof drug-coated core seeds with a seal coat mixture prior to forming theextended release-coated core seeds; wherein the seal coat mixturecomprises one or more film-forming polymers and solvent, and wherein theseal coat mixture comprises less than 1 wt % organic solvent; andwherein the oral pharmaceutical composition comprises a core seed; adrug coating layer comprising amantadine, or a pharmaceuticallyacceptable salt thereof, a seal coating layer, an extended releasecoating layer; and wherein the plurality of extended release-coated coreseeds comprises than 6000 ppm organic solvent. In some embodiments, theprocess includes a plurality of drying steps, for example a drying stepbetween each coating application. In some embodiments, thepharmaceutical composition comprises less than 6000 ppm organic solvent.

The coating steps of the process, for example coating of the core seedsor the drug-core seeds, may involve applying a mixture as describedherein (for example, a drug mixture, an extended release mixture, or aseal coat mixture) by any suitable means. The coating may includespraying or otherwise applying the mixture to the core seeds, or coatedcore seeds, such that at least a portion of the seeds are surrounded bya portion of the mixture. In some embodiments, coating a core seed (or acoated core seed) includes fully surrounding the core seed by a mixtureas described herein. In other embodiments, coating the seed comprisessurrounding almost all of the core seed, or the majority of the coreseed, for example wherein at least 90%, at least 95%, at least 98%, atleast 99%, or at least 99.9% of the surface area the core seed issurrounded by the coating. The mixture may be applied in uniformthickness, or may vary in thickness.

In some embodiments, the organic solvent is a linear or cyclic ketone(e.g., acetone, methyl ethyl ketone, etc.) In some embodiments, theorganic solvent is a sulfoxide (e.g., dimethyl sulfoxide, etc.). In someembodiments, the organic solvent is an amide (e.g., dimethyl formamide,N-methyl pyrrolidone, hexamethyl phosphorous triamide (HMPT), etc.). Insome embodiments, the organic solvent is a linear or cyclic ether (e.g.,tetrahydrofuran, diethyl ether, bis(2-methoxyethyl) ether (diglyme),dimethoxy ethane (glyme), 1,4-dioxane, etc.). In some embodiments, theorganic solvent is a phosphoramide (e.g., hexamethyl phosphoramide(HPMA), etc.). In some embodiments, the organic solvent is a chlorinatedhydrocarbon (e.g., chloroform, dichloromethane, dichloroethane, carbontetrachloride, etc.). In some embodiments, the organic solvent is aglycol (e.g., ethylene glycol, diethylene glycol, propylene glycol,etc.). In some embodiments, the organic solvent is a,nitrogen-containing solvent (e.g., pyridine, acetonitrile, etc.). Insome embodiments, the organic solvent is an alcohol (e.g., a C₁-C₆alcohol (e.g., ethanol, methanol, isopropanol, 1-butanol, 2-butanol,glycerol), such as isopropyl alcohol. In some embodiments, mixtures oftwo or more solvents can be used. In some embodiments, reducing oravoiding the use of organic solvent in the drug coating mixture and theoptional seal coating mixture, while still using organic solvent in theextended release coating mixture can produce a pharmaceuticalcomposition as described herein comprising a plurality of coated coreseeds, for example extended-release coated core seeds as describedherein, with less than 6000 ppm, less than 5500 ppm, less than 5000 ppm,less than 4500 ppm, less than 4000 ppm, less than 3500 ppm, less than3000 ppm, less than 2500 ppm, less than 2000 ppm, less than 1500 ppm, orless than 1200 ppm organic solvent. In some embodiments of the levels oforganic solvent described herein, the provided level refers to the totalamount of two or more organic solvents.

The components of each coating mixture may be any of the componentsdescribed herein for the coatings of the pharmaceutical composition. Forexample, in some embodiments, the one or more pharmaceuticallyacceptable excipients comprise one or more binders and one or moreanti-tack agents; and the extended release mixture further comprises aplasticizer, and a pore-forming agent. In other embodiments, the drugmixture comprises hydroxpropyl methyl cellulose, copovidone, talc, andsolvent; and the extended release mixture comprises ethyl cellulose,povidone, medium chain triglycerides, and solvent. In still furtherembodiments, the seal coat mixture comprises hydroxypropyl methylcellulose, talc, and solvent. In some embodiments, the solvent in theseal coat mixture is water. In other embodiments, the solvent in theextended release mixture comprises alcohol and water. In still furtherembodiments, the solvent in the drug mixture is water.

The processes provided herein may produce an oral pharmaceuticalcomposition comprising a plurality of coated core seeds, wherein theplurality of coated core seeds comprises less than 6000 ppm, less than5500 ppm, less than 5000 ppm, less than 4500 ppm, less than 4000 ppm,less than 3500 ppm, less than 3000 ppm, less than 2500 ppm, less than2000 ppm, less than 1500 ppm, or less than 1200 ppm organic solvent. Insome embodiments, the coated core seeds are extended-release coated coreseeds.

The process provided herein may produce a pharmaceutical compositioncomprising any components, in any weights, ratios, or weight percent, asdescribed herein. For example, in some embodiments of the processprovided herein, the oral pharmaceutical composition comprises:

-   -   between 30 wt % to 60 wt % amantadine, or a pharmaceutically        acceptable salt thereof,    -   between 1 wt % to 25 wt % hydroxypropyl methyl cellulose;    -   between 1 wt % and 4 wt % copovidone;    -   between 10 wt % to 20 wt % ethyl cellulose;    -   between 0.25 wt % to 4 wt % medium triglycerides;    -   between 0.25 wt % to 4 wt % povidone; and    -   the plurality of coated core seeds comprise less than 2000 ppm        of alcohol.

In some embodiments, the pharmaceutical composition comprises less than2000 ppm organic solvent, such as alcohol. In certain embodiments, thepharmaceutical composition comprises a plurality of coated core seeds,wherein the plurality of coated core seeds comprise less than 2000 ppmorganic solvent, such as alcohol. In some embodiments of the process asprovided herein, the oral pharmaceutical composition comprises coreseeds comprising microcrystalline cellulose from 5 wt % to 20 wt %, orfrom 10 wt % to 15 wt %, or about 12.44 wt % of the composition; a drugcoating surrounding each core seed, wherein the drug coating comprisesamantadine, or a pharmaceutically acceptable salt thereof from 20 wt %to 60 wt %, or from 30 wt % to 50 wt %, or from 40 wt % to 50 wt %, orabout 43.54 wt % of the composition; the pharmaceutically acceptableexcipients hydroxypropyl methyl cellulose from 5 wt % to 18 wt %, orfrom 8 wt % to 15 wt %, or about 11.61 wt %, and copovidone at from 1 wt% to 5 wt %, or from 2 wt % to 4 wt %, or about 2.9 wt % of thecomposition; and the anti-tack agent talc at from 1 wt % to 3 wt %, orfrom 1.5 wt % to 2.5 wt %, or about 2.17 wt % of the composition; anextended release coating surrounding the drug coating, wherein theextended release coating comprises the release modifying excipient ethylcellulose from 5 wt % to 25 wt %, or 10 wt % to 20 wt %, or about 15.91wt % of the composition; the pore forming agent povidone at from 1 wt %to 3 wt %, or from 1.5 wt % go 2.5 wt %, or about 2.15 wt % of thecomposition; and the plasticizer medium chain triglycerides from 1 wt %to 3 wt %, or from 1.5 wt % go 2.5 wt %, or about 2.15 wt % of thecomposition; and a seal coating surrounding the drug coating, whereinthe extended release coating surrounds the seal coating, and the sealcoating comprises the film-forming polymer hydroxpropyl methyl cellulosefrom 3 wt % to 10 wt %, or 5 wt % to 8 wt %, or about 6.6 wt % of thecomposition; and the anti-tack agent talc at from 0.25 wt % to 1 wt %,or from 0.5 wt % to 0.75 wt %, or about 0.66 wt % of the composition. Insome embodiment, the amantadine or a pharmaceutically acceptable saltthereof is amantadine hydrochloride. In certain embodiments, the oralpharmaceutical composition further comprises magnesium stearate from0.01 wt % to 0.2 wt %, or 0.08 wt % to 0.12 wt %, or about 0.1 wt % ofthe composition. In some embodiments, the pharmaceutically acceptablesalt of amantadine is amantadine hydrochloride. In another embodiment,the pharmaceutically acceptable salt of amantadine is amantadinesulfate.

In some embodiments, the plurality of core seeds surrounded by a drugcoating and optionally a seal coating comprises between 70 wt % to 90 wt%, between 75 wt % to 85 wt %, or about 80.57 wt % of the finalcomposition, and an extended release coating is applied to increase thetotal weight by about 24%. In other embodiments, the plurality of coreseeds surrounded by a drug coating and optionally a seal coatingcomprises between 70 wt % to 90 wt %, between 75 wt % to 85 wt %, orabout 79.92 wt % of the final composition, and an extended releasecoating is applied to increase the total weight by about 25%. In certainembodiments, an oral pharmaceutical composition with an increased wt %of extended release coating (for example, increased about 2 wt %, about1.5 wt %, about 1 wt %, or about 0.5 wt %), results in a lower incidenceof gastrointestinal effects compared to a composition with a lower wt %of extended release coating.

Further provided herein is an oral pharmaceutical composition formed byany of the processes described herein. Also provided herein is an oralpharmaceutical composition capable of being formed by any of theprocessed provided herein.

IV. Other Extended Release Dosage Forms

The person of skill in the art will recognize that other embodiments ofextended release oral compositions may be envisioned, in addition to thecapsule formulation described herein. Such other embodiments includeextended release solid dosage forms, such as tablets, capsules, gelcaps, powders, pellets, beadlets, etc. Included in such extended releasecompositions are those that have the release characteristics and in vivopharmacokinetic profile to be employed in the methods of the disclosure.In some embodiments, the person skilled in the art may employ, withappropriate adjustment of design characteristics to achieve thenecessary pharmacokinetic profile described herein, the extended releasetechnology described in U.S. Pat. No. 5,358,721, to Guittard et al., orU.S. Pat. No. 6,217,905, to Edgren et al., each of which disclose anoral osmotic dosage form of amantadine, and each of which isincorporated herein by reference in its entirety. In other embodiments,the person of skill in the art may employ, again with appropriateadjustment of design characteristics, the technology described in U.S.Pat. No. 6,194,000, to Smith et al. or U.S. Patent Appl. PublicationNos. US 2006/0252788, US 2006/0189694, US 2006/0142398, US 2008/0227743,US2011/0189273 and US20150087721, all to Went et al., each of whichdisclose the administration of an NMDA receptor antagonist, such asamantadine, optionally in controlled release form, and each of which isincorporated herein by reference in its entirety.

Some embodiments herein provide a method of once nightly orallyadministering amantadine (or a pharmaceutically acceptable salt thereof,such as amantadine hydrochloride) to a subject in need thereof, saidmethod comprising orally administering an extended release (ER)composition comprising amantadine, or a pharmaceutically acceptable saltthereof, less than four hours before bedtime (and/or after 4 p.m.). Insome embodiments, administration occurs less than four hours beforebedtime. In some such methods, the method increases the ON time withoutdyskinesia experienced by the Parkinson's disease subject. In some suchmethods, the method reduces the ON time with dyskinesia experienced bythe Parkinson's disease subject. In some such methods, the methodreduces the ON time with troublesome dyskinesia experienced by theParkinson's disease subject. In some embodiments, the method reduces theOFF time experienced by the Parkinson's disease subject. In someembodiments, the method increases ON time without troublesomedyskinesia, and does so without inducing or increasing sleepdisturbances in the Parkinson's disease subject. In some embodiments,the method improves clinician global impression, and does so withoutinducing or increasing sleep disturbances in the subject. In someembodiments, the composition is added to food prior to administration.In some embodiments, there is no increase in plasma concentration ofamantadine for at least one hour after the administration. In someembodiments, there is no increase in plasma concentration of amantadinefor at least two hours after the administration. In some embodiments,the amantadine has a single dose Tmax of 9 to 18 hours, and/or a steadystate Tmax of 7 to 13 hours. In some embodiments, the amantadine has asingle dose Tmax of 12 to 18 hours after administration, and/or a steadystate Tmax of 8 to 12 hours. In some embodiments, the amantadine has asingle dose Tmax of 12 to 16 hours after administration, and/or a steadystate Tmax of 9 to 12 hours. In some embodiments, a once nightly oraladministration of the composition to a human subject provides a steadystate plasma concentration profile characterized by a concentrationincrease of amantadine of less than 25% at three hours after theadministration. In some embodiments, the PK curve has a Cmax/Cmin ratioof 1.4 to 1.9. In some embodiments, the ratio of C-ave-day/C-ave nightat steady state is 1.2 to 1.7. In some embodiments, the averageamantadine plasma concentration during the day (C-ave-day) at steadystate is 500-2000 ng/ml. In some embodiments, the amantadine isamantadine hydrochloride or amantadine sulfate. In some embodiments, thecomposition comprises 260 to 420 mg of amantadine hydrochloride. In someembodiments, the composition is administered as two, or three or fourunit dosage forms each comprising 85 to 175 mg amantadine hydrochloride.In some embodiments, the composition is administered as two unit dosageforms each comprising 130 to 210 mg of extended release amantadinehydrochloride. In some embodiments, the composition is within a capsuleof capsule size #1. In some embodiments, the composition comprises 260mg to 340 mg of amantadine or an equivalent amount of a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprises340 mg of a pharmaceutically acceptable salt of amantadine, such asamantadine hydrochloride. In some embodiments, the composition comprises170 mg amantadine hydrochloride. In some embodiments, oraladministration of a single dose of the composition to a human subject ina fasted state provides a maximum plasma concentration (Cmax) of 1.1 to2.1 ng/ml per mg of amantadine, and an AUC_(0-inf) of 42 to 72 ng*h/mLper mg of amantadine. In some embodiments, once nightly oraladministration of a dose of the composition to a human subject providesa steady state plasma concentration profile characterized by: (a) a Cmaxof 2.0 to 3.1 ng/ml per mg of amantadine; (b) a Cmin of 1.3 to 2.0 ng/mlper mg of amantadine, and (c) an AUC₀₋₂₄ of 42 to 68 ng*h/mL per mg ofamantadine. In some embodiments, the steady state plasma concentrationprofile is further characterized by: (d) no increase in plasmaconcentration of amantadine for at least one hour after theadministration; and (e) a Cmax/Cmin ratio of 1.4 to 1.9. In someembodiments, the steady state plasma concentration profile is furthercharacterized by: (f) no increase in concentration of amantadine for atleast two hours after the administration; and (g) a Cmax/Cmin ratio of1.4 to 1.9.

In some embodiments, the composition has an AUC profile afteradministration of a single dose of the composition characterized by: afractional AUC from 0 to 4 hours that is less than 0.25% of AUC_(0-inf);a fractional AUC from 0 to 8 hours that is less than 3.5% ofAUC_(0-inf); a fractional AUC from 0 to 12 hours that is about 5 to 12%of AUC_(0-inf); a fractional AUC from 0 to 18 hours that is about 25 to60% of AUC_(0-inf); and a fractional AUC from 0 to 24 hours that isabout 20 to 27% of AUC_(0-inf). In some embodiments, the composition hasan AUC profile after once nightly dosing of the composition at steadystate conditions characterized by: a fractional AUC from 0 to 4 hoursthat is about 2 to 25% of AUC₀₋₂₄; a fractional AUC from 0 to 8 hoursthat is about 15 to 50% of AUC₀₋₂₄; a fractional AUC from 0 to 12 hoursthat is about 30 to 70% of AUC₀₋₂₄: and a fractional AUC from 0 to 18hours that is about 60 to 95% of AUC₀₋₂₄. In some such embodiments, themethod increases ON time without troublesome dyskinesia. In some suchembodiments, the method decreases OFF time experienced by a Parkinson'ssubject.

Some embodiments herein provide a method of reducing sleep disturbancein a human subject undergoing treatment with amantadine, said methodcomprising once nightly orally administering an extended release (ER)composition comprising amantadine, or a pharmaceutically acceptable saltthereof, less than four hours before bedtime (and/or after 4 p.m.). Insome such methods, the method reduces the ON time the Parkinson'sdisease subject experiences with dyskinesia. In some such methods, themethod reduces the ON time with troublesome dyskinesia experienced bythe Parkinson's disease subject. In some embodiments, the method reducesthe OFF time the Parkinson's disease subject experiences. In someembodiments, the method increases ON time without troublesomedyskinesia, and does so without inducing or increasing sleepdisturbances or gastrointestinal adverse events in the Parkinson'sdisease subject. In some embodiments, the composition is added to foodprior to administration. In some embodiments, there is no increase inplasma concentration of amantadine for at least one hour after theadministration. In some embodiments, the composition is added to foodprior to administration. In some embodiments, there is no increase inplasma concentration of amantadine for at least one hour after theadministration. In some embodiments, there is no increase in plasmaconcentration of amantadine for at least two hours after theadministration.

In some embodiments of the methods described herein, for example methodsof administration, or reducing one or more side effects, or treating onemore symptoms, the unit dosage of amantadine is from 40 mg to 500 mg, 45mg to 400 mg, from 50 mg to 350 mg, from 55 mg to 300 mg, from 60 mg to290 mg, from 68.5 mg to 274 mg, from 50 mg to 80 mg, from 55 mg to 75mg, from 60 mg to 70 mg, from 120 mg to 150 mg, from 135 mg to 145 mg,from 130 mg to 140 mg, from 250 mg to 300 mg, from 260 mg to 290 mg,from 270 mg to 280 mg, about 68.5 mg, about 137 mg, or about 274 mg, oran equivalent amount of a pharmaceutically acceptable salt ofamantadine. In some embodiments, the pharmaceutically acceptable salt ofamantadine is amantadine hydrochloride. In another embodiment, thepharmaceutically acceptable salt of amantadine is amantadine sulfate. Itshould be clear to one of skill in the art how to calculate an“equivalent amount” of the salt of a compound, taking into account thatthe salt has an increased molecular weight. For example, in someembodiments, the methods comprise administering about 68.5 mg ofamantadine, or an equivalent amount of the amantadine hydrochloridesalt. Thus, in some embodiments, the method comprises administeringabout 85 mg of amantadine hydrochloride. The unit dosage may be in asingle capsule, or it may be across multiple capsules.

Pharmacokinetic parameters that are recited herein on a “per mg of drug”basis may be calculated using the mg of the form of amantadine in thecomposition. Thus, for example, if the composition comprises amantadine,the calculation could use the weight of amantadine present. If thecomposition comprises a pharmaceutically acceptable salt of amantadine,the calculation could use the weight of the pharmaceutically acceptablesalt. Furthermore, a person of skill in the art know how to convert thevalue of a pharmacokinetic parameter that was calculated using theweight of one form (e.g., amantadine or a pharmaceutically acceptablesalt of amantadine) to the value that corresponds the use of anotherform. Thus, for example, parameters reciting or based on the weight ofamantadine could be converted to parameters reciting or based on theweight of a pharmaceutically acceptable salt of amantadine, for exampleamantadine hydrochloride. Examples of such parameters may includeAUC_(inf) with units of ng*hr/ml per mg; pAUC₀₋₆ with units of ng*hr/mlper mg; pAUC₀₋₈ with units of ng*hr/ml per mg; mean Cmax with units ofng/ml per mg; mean Cmin with units of ng/ml per mg; or mean AUC₀₋₂₄ withunits of ng*h/mL per mg.

ENUMERATED EMBODIMENTS

Embodiment I-1. An oral pharmaceutical composition, comprising:

-   -   from 137 mg to 500 mg of amantadine or a pharmaceutically        acceptable salt thereof, and    -   at least one excipient that modifies the release of said drug,    -   wherein said pharmaceutical composition has (i) a Tmax for        amantadine of 11 to 19 hours, (ii) an AUC_(0-inf) for amantadine        of 44 to 72 ng*hr/ml per mg of said drug, and (iii) a pAUC₀₋₈        for amantadine of 1.0 to 2.0 ng*hr/ml per mg of said drug, when        said pharmaceutical composition is dosed in healthy subjects of        a single dose, fasting human pharmacokinetic study.

Embodiment I-2. An oral pharmaceutical composition, comprising:

-   -   from 137 mg to 500 mg of amantadine or a pharmaceutically        acceptable salt thereof, and    -   at least one excipient that modifies the release of the        amantadine or the pharmaceutically acceptable salt thereof;    -   wherein said pharmaceutical composition has (i) a Tmax for        amantadine of 11 to 19 hours, (ii) an AUC_(0-inf) for amantadine        of 44 to 72 ng*hr/ml per mg of said drug, and (iii) a pAUC₀₋₆        for amantadine of 0.3 to 0.9 ng*hr/ml per mg of said drug, when        said pharmaceutical composition is dosed in healthy subjects of        a single dose, fasting human pharmacokinetic study.

Embodiment I-3. The oral pharmaceutical composition of embodiment I-1,wherein the oral pharmaceutical composition has a pAUC₀₋₆ for amantadineof 0.3 to 0.9 ng*hr/ml per mg of said drug when dosed in healthysubjects of a single dose, fasting human pharmacokinetic study.

Embodiment I-4. An oral pharmaceutical composition, comprising:

-   -   from 137 mg to 500 mg of amantadine or a pharmaceutically        acceptable salt thereof, and    -   at least one excipient that modifies the release of the        amantadine or the pharmaceutically acceptable salt thereof,    -   wherein said oral pharmaceutical composition has a dissolution        profile of amantadine which shows at least 3 of (i) 0% to 10% in        2 hours, (ii) 3% to 14% in 4 hours, (iii) 23% to 40% in 6        hours, (iv) 50% to 70% in 8 hours, and (v) not less than 80% in        12 hours as determined in a USP Type 2 apparatus (paddles) at 50        rpm at 37.0±0.5° C. with 500 ml water as the dissolution medium,        and    -   wherein said oral pharmaceutical composition has (i) a Tmax for        amantadine of 11 to 19 hours, and (ii) an AUC_(0-inf) for        amantadine of 44 to 72 ng*hr/ml per mg of said drug, when said        oral pharmaceutical composition is dosed in healthy subjects of        a single dose, fasting human pharmacokinetic study.

Embodiment I-5. The oral pharmaceutical composition of embodiment I-4,wherein said dissolution profile is (i) 0% to 9% in 2 hours, (ii) 3% to14% in 4 hours, (iii) 24% to 40% in 6 hours, (iv) 45% to 70% in 8 hours,and (v) not less than 82% in 12 hours.

Embodiment I-6. A method for administering an oral pharmaceuticalcomposition to a subject in need thereof, comprising:

-   -   orally administering to said patient once daily, 0 to 4 hours        before bedtime, an oral pharmaceutical composition,    -   wherein the oral pharmaceutical composition comprises from 137        mg to 500 mg of amantadine or a pharmaceutically acceptable salt        thereof, and    -   at least one excipient that modifies the release of the        amantadine or pharmaceutically acceptable salt thereof, and    -   wherein said oral pharmaceutical composition has (i) a Tmax for        amantadine of 11 to 19 hours, (ii) an AUC_(0-inf) for amantadine        of 44 to 72 ng*hr/ml per mg of said drug, and (iii) a pAUC₀₋₈        for amantadine of 1.0 to 2.0 ng*hr/ml per mg of said drug, when        said pharmaceutical composition is dosed in healthy subjects of        a single dose, fasting human pharmacokinetic study.

Embodiment I-7. A method for administering an oral an oralpharmaceutical composition to a subject in need thereof, comprising:

-   -   orally administering to a subject once daily, 0 to 4 hours        before bedtime, a pharmaceutical composition,    -   wherein the oral pharmaceutical composition comprises from 137        mg to 500 mg of amantadine or a pharmaceutically acceptable salt        thereof, and    -   at least one excipient that modifies the release of the        amantadine or the pharmaceutically acceptable salt thereof, and    -   wherein said oral pharmaceutical composition has (i) a Tmax for        amantadine of 11 to 19 hours, (ii) an AUC_(0-inf) for amantadine        of 44 to 72 ng*hr/ml per mg of said drug, and (iii) a pAUC₀₋₆        for amantadine of 0.3 to 0.9 ng*hr/ml per mg of said drug, when        said oral pharmaceutical composition is dosed in healthy        subjects of a single dose, fasting human pharmacokinetic study.

Embodiment I-8. The method of embodiment I-6, wherein the oralpharmaceutical composition has a pAUC₀₋₆ for amantadine of 0.3 to 0.9ng*hr/ml per mg of said drug when dosed in healthy subjects of a singledose, fasting human pharmacokinetic study.

Embodiment I-9. A method for administering an oral pharmaceuticalcomposition to a subject in need thereof, comprising:

-   -   orally administering to a subject once daily, 0 to 4 hours        before bedtime, a oral pharmaceutical composition,    -   wherein the oral pharmaceutical composition comprises from 137        mg to 500 mg amantadine or a pharmaceutically acceptable salt        thereof, and    -   at least one excipient that modifies the release of the        amantadine or the pharmaceutically acceptable salt thereof;    -   wherein the oral pharmaceutical composition has a dissolution        profile of amantadine which shows at least 3 of (i) 0% to 10% in        2 hours, (ii) 3% to 14% in 4 hours, (iii) 23% to 40% in 6        hours, (iv) 50% to 70% in 8 hours, and (v) not less than 80% in        12 hours as determined in a USP Type 2 apparatus (paddles) at 50        rpm at 37.0±0.5° C. with 500 ml water as the dissolution medium,        and    -   wherein the oral pharmaceutical composition has (i) a Tmax for        amantadine of 11 to 19 hours, and (ii) an AUC_(0-inf) for        amantadine of 44 to 72 ng*hr/ml per mg of said drug, when said        oral pharmaceutical composition is dosed in healthy subjects of        a single dose, fasting human pharmacokinetic study.

Embodiment I-10. The method of embodiment I-9, wherein said dissolutionprofile is (i) 0% to 9% in 2 hours, (ii) 3% to 14% in 4 hours, (iii) 24%to 40% in 6 hours, (iv) 45% to 70% in 8 hours, and (v) not less than 82%in 12 hours.

Embodiment I-11. A method for reducing gastrointestinal adverse eventsin a subject orally administered a pharmaceutical composition comprisingamantadine or a pharmaceutically acceptable salt thereof, comprising:

-   -   orally administering to a subject an oral pharmaceutical        composition comprising from 137 mg to 500 mg of amantadine or a        pharmaceutically acceptable salt thereof, and    -   at least one excipient that modifies the release of the        amantadine or the pharmaceutically acceptable salt thereof,    -   wherein the oral pharmaceutical composition has (i) a Tmax for        amantadine of 11 to 19 hours, (ii) an AUC_(0-inf) for amantadine        of 44 to 72 ng*hr/ml per mg of said drug, and (iii) a pAUC₀₋₈        for amantadine of 1.0 to 2.0 ng*hr/ml per mg of said drug, when        the oral pharmaceutical composition is dosed in healthy subjects        of a single dose, fasting human pharmacokinetic study.

Embodiment I-12. A method for reducing gastrointestinal adverse eventsin a subject orally administered an oral pharmaceutical compositioncomprising amantadine or a pharmaceutically acceptable salt thereof,comprising:

-   -   orally administering to a subject an oral pharmaceutical        composition comprising from 137 mg to 500 mg of amantadine or a        pharmaceutically acceptable salt thereof, and    -   at least one excipient that modifies the release of the        amantadine or the pharmaceutically acceptable salt thereof,    -   wherein the oral pharmaceutical composition has (i) a Tmax for        amantadine of 11 to 19 hours, (ii) an AUC_(0-inf) for amantadine        of 44 to 72 ng*hr/ml per mg of said drug, and (iii) a pAUC₀₋₆        for amantadine of 0.3 to 0.9 ng*hr/ml per mg of said drug, when        the oral pharmaceutical composition is dosed in healthy subjects        of a single dose, fasting human pharmacokinetic study.

Embodiment I-13. The method of embodiment I-11, wherein the oralpharmaceutical composition has a pAUC₀₋₆ for amantadine of 0.3 to 0.9ng*hr/ml per mg of said drug when dosed in healthy subjects of a singledose, fasting human pharmacokinetic study.

Embodiment I-14. A method for reducing gastrointestinal adverse eventsin a subject orally administered a pharmaceutical composition comprisingamantadine or a pharmaceutically acceptable salt thereof, comprising:

-   -   orally administering to a subject an oral pharmaceutical        composition comprising from 137 mg to 500 mg of amantadine or a        pharmaceutically acceptable salt thereof, and    -   at least one excipient that modifies the release of the        amantadine or the pharmaceutically acceptable salt thereof,    -   wherein the oral pharmaceutical composition has a dissolution        profile of amantadine which shows at least 3 of (i) 0% to 10% in        2 hours, (ii) 3% to 14% in 4 hours, (iii) 23% to 40% in 6        hours, (iv) 50% to 70% in 8 hours, and (v) not less than 80% in        12 hours as determined in a USP Type 2 apparatus (paddles) at 50        rpm at 37.0±0.5° C. with 500 ml water as the dissolution medium,        and    -   wherein said oral pharmaceutical composition has (i) a Tmax for        amantadine of 11 to 19 hours, and (ii) an AUC_(0-inf) for        amantadine of 44 to 72 ng*hr/ml per mg of said drug, when said        pharmaceutical composition is dosed in healthy subjects of a        single dose, fasting human pharmacokinetic study.

Embodiment I-15. The method of embodiment I-14, wherein said dissolutionprofile is (i) 0% to 9% in 2 hours, (ii) 3% to 14% in 4 hours, (iii) 24%to 40% in 6 hours, (iv) 45% to 70% in 8 hours, and (v) not less than 82%in 12 hours.

Embodiment I-16. A process of preparing an oral pharmaceuticalcomposition comprising amantadine, or a pharmaceutically acceptable saltthereof, comprising:

-   -   a) coating a plurality of core seeds with a drug mixture to form        a drug-coated core seed,        -   wherein the drug mixture comprises amantadine or a            pharmaceutically acceptable salt thereof, one or more            pharmaceutically acceptable excipients, and solvent, and        -   wherein the drug mixture comprises less than 1 wt % organic            solvent;    -   b) coating the plurality of drug-coated core seeds with an        extended release mixture to form extended-release coated core        seeds,        -   wherein the extended release mixture comprises one or more            release modifying excipients and solvent;    -   c) drying the plurality of extended release-coated core seeds;        and    -   d) encapsulating the plurality of extended release-coated core        seeds in a capsule shell to produce the oral pharmaceutical        composition,        -   wherein the oral pharmaceutical composition comprises a core            seed, a drug        -   coating comprising amantadine, or a pharmaceutically            acceptable salt thereof, an extended release coating, and        -   the plurality of extended release-coated core seeds comprise            less than 6000 ppm organic solvent.

Embodiment I-17. The process of embodiment I-16, further comprising:

-   -   coating the plurality of drug-coated core seeds with a seal coat        mixture prior to forming the extended release-coated core seeds,    -   wherein the seal coat mixture comprises one or more film-forming        polymers and solvent, and    -   wherein the seal coat mixture comprises less than 1 wt % organic        solvent; and        -   wherein the oral pharmaceutical composition comprises a core            seed; a drug coating comprising amantadine, or a            pharmaceutically acceptable salt thereof, a seal coating, an            extended release coating;        -   the plurality of extended release-coated core seeds comprise            less than 6000 ppm organic solvent.

Embodiment I-18. The process of embodiment I-16 or I-17, wherein theorganic solvent is an alcohol.

Embodiment I-19. The process of any one of embodiments I-16 to I-18,wherein the organic solvent is isopropyl alcohol.

Embodiment I-20. The process of any one of embodiments I-16 to I-19,wherein the one or more pharmaceutically acceptable excipients compriseone or more binders and one or more anti-tack agents; and the extendedrelease mixture further comprises a plasticizer and a pore-formingagent.

Embodiment I-21. The process of any one of embodiments I-16 to I-20,wherein the drug mixture comprises hydroxpropyl methyl cellulose,copovidone, talc, and solvent; and the extended release mixturecomprises ethyl cellulose, povidone, medium chain triglycerides, andsolvent.

Embodiment I-22. The process of any one of embodiments I-17 to I-21,wherein the seal coat mixture comprises hydroxypropyl methyl cellulose,talc, and solvent.

Embodiment I-23. The process of any one of embodiments I-16 to I-22,wherein the plurality of extended-release coated core seeds comprisesless than 2000 ppm of organic solvent.

Embodiment I-24. The process of any one of embodiments I-16 to I-23,wherein the oral pharmaceutical composition comprises:

-   -   between 30 wt % to 60 wt % amantadine, or a pharmaceutically        acceptable salt thereof,    -   between 1 wt % to 25 wt % hydroxypropyl methyl cellulose;    -   between 1 wt % and 4 wt % copovidone;    -   between 10 wt % to 20 wt % ethyl cellulose;    -   between 0.25 wt % to 4 wt % medium triglycerides;    -   between 0.25 wt % to 4 wt % povidone; and    -   wherein the plurality extended-release coated core seeds        comprises than 2000 ppm of alcohol.

Embodiment I-25. The process of any one of embodiments I-16 to I-24,wherein the solvent in the drug mixture comprises water.

Embodiment I-26. The process of embodiment I-25, wherein the solvent inthe drug mixture comprises greater than 99 wt % water.

Embodiment I-27. The process of embodiment I-25 or claim I-26, whereinthe solvent in the drug mixture is water.

Embodiment I-28. The process of any one of embodiments I-17 to I-27,wherein the solvent in the seal coat mixture comprises water.

Embodiment I-29. The process of embodiment I-28, wherein the solvent inthe seal mixture comprises greater than 99 wt % water.

Embodiment I-30. The process of embodiment I-28 or I-29, wherein thesolvent in the seal mixture is water.

Embodiment I-31. The process of any one of embodiments I-16 to I-30,wherein the solvent in the extended release mixture comprises water.

Embodiment I-32. The process of any one of embodiments I-16 to I-30,wherein the solvent in the extended release mixture comprises an organicsolvent.

Embodiment I-33. The process of any one of embodiments I-16 to I-32,wherein the solvent in the extended release mixture comprises water andan organic solvent.

Embodiment I-34. The process of embodiment I-33, wherein the solvent inthe extended release mixture comprises water and up to 50 wt % of anorganic solvent.

Embodiment I-35. An oral pharmaceutical composition formed by theprocess of any one of embodiments I-16 to I-34.

Embodiment I-36. An oral pharmaceutical composition capable of beingformed by the process of any one of embodiments I-16 to I-35.

Embodiment I-37. An oral pharmaceutical composition comprisingamantadine, or a pharmaceutically acceptable salt thereof, comprising:

-   -   a plurality of coated core seeds, wherein each coated core seed        comprises:        -   a core seed,        -   a drug coating surrounding the core seed, wherein the drug            coating comprises amantadine, or a pharmaceutically            acceptable salt thereof and one or more pharmaceutically            acceptable excipients; and an extended release coating            surrounding the drug coating, wherein the extended release            coating comprises one or more release modifying excipients;            and    -   a capsule shell, wherein the plurality of coated core seeds is        encapsulated within the capsule shell; and,    -   wherein the plurality of coated core seeds comprises less than        6000 ppm organic solvent.

Embodiment I-38. The oral pharmaceutical composition of embodiment I-37,wherein the organic solvent is an alcohol.

Embodiment I-39. The oral pharmaceutical composition of embodiment I-37or I-38, wherein the organic solvent is isopropyl alcohol.

Embodiment I-40. The oral pharmaceutical composition of any one ofembodiments I-37 to I-39, further comprising a seal coating surroundingthe drug coating, wherein the seal coating comprises one or morefilm-forming polymers and is surrounded by the extended release coating.

Embodiment I-41. The oral pharmaceutical composition of any one ofembodiments I-37 to I-40, wherein the one or more pharmaceuticallyacceptable excipients comprise one or more binders and one or moreanti-tack agents, and the extended release coating further comprises aplasticizer and a pore-forming agent.

Embodiment I-42. The oral pharmaceutical composition of any one ofembodiments I-37 to I-41, wherein:

-   -   the one or more pharmaceutically acceptable excipients comprise        one or more binders and one or more anti-tack agents, wherein        the one or more binders comprise hydroxpropyl methyl cellulose        and copovidone, and the one or more anti-tack agents comprise        talc; and    -   the extended release coating comprises a release modifying        excipient, a plasticizer, a pore-forming agent,        -   wherein the release modifying excipient comprises ethyl            cellulose, the pore forming agent comprises povidone, and            the plasticizer comprises medium chain triglycerides.

Embodiment I-43. The oral pharmaceutical composition of any one ofembodiments I-40 to I-42, wherein the film-forming polymer compriseshydroxypropyl methyl cellulose, and the seal coating further comprisestalc.

Embodiment I-44. The oral pharmaceutical composition of any one ofembodiments I-37 to I-43, wherein plurality of coated core seedscomprise less than 2000 ppm of organic solvent.

Embodiment I-45. The oral pharmaceutical composition of any one ofembodiments I-37 to I-44, wherein the pharmaceutical compositioncomprises:

-   -   between 30 wt % to 60 wt % amantadine or a pharmaceutically        acceptable salt thereof;    -   between 1 wt % to 25 wt % hydroxypropyl methyl cellulose;    -   between 1 wt % and 4 wt % copovidone;    -   between 10 wt % to 20 wt % ethyl cellulose;    -   between 0.25 wt % to 4 wt % medium triglycerides;    -   between 0.25 wt % to 4 wt % povidone; and the plurality of        coated core seeds comprises than 2000 ppm of alcohol.

Embodiment I-46. The oral pharmaceutical composition of any one ofembodiments I-37 to I-45, wherein:

the drug coating comprises:

-   -   between 40 wt % to 50 wt % of amantadine or a pharmaceutically        acceptable salt thereof;    -   between 10 wt % to 15 wt % of hydroxypropyl methyl cellulose;    -   between 2 wt % to 3.5 wt % of copovidone; and    -   between 1.8 wt % to 2.5 wt % of talc; and        the extended release coating comprises:    -   between 10 wt % to 20 wt % of ethyl cellulose;    -   between 1.5 wt % to 2.5 wt % povidone; and    -   between 1.5 wt % to 2.5 wt % medium chain triglycerides.

Embodiment I-47. The oral pharmaceutical composition of any one ofembodiments I-37 to I-46, wherein the seal coating comprises between 5wt % to 10 wt % hydroxypropyl methyl cellulose and between 0.25 wt % to1 wt % talc.

Embodiment I-48. The oral pharmaceutical composition of any one ofembodiments I-37 to I-47, wherein the unit dose of amantadine is between40 mg to 500 mg, or an equivalent amount of a pharmaceuticallyacceptable salt thereof.

Embodiment I-49. The oral pharmaceutical composition of any one ofembodiments I-37 to I-48, wherein the unit dose of amantadine is between60 mg to 300 mg, or an equivalent amount of a pharmaceuticallyacceptable salt thereof.

Embodiment I-50. The oral pharmaceutical composition of any one ofembodiments I-37 to I-49, wherein the oral pharmaceutical composition isformulated for once-daily administration.

Embodiment II-1. An oral pharmaceutical composition, comprising:

-   -   a drug, wherein the drug is amantadine or a pharmaceutically        acceptable salt thereof, and wherein said oral pharmaceutical        composition comprises from 50 mg to 500 mg of the amantadine or        an equivalent amount of the pharmaceutically acceptable salt        thereof; and    -   at least one excipient that modifies the release of at least a        portion of said drug;    -   wherein said oral pharmaceutical composition has a dissolution        profile of said drug which shows at least four of:        -   (i) 0% to 10% in 2 hours,        -   (ii) 3% to 14% in 4 hours,        -   (iii) 23% to 40% in 6 hours,        -   (iv) 50% to 70% in 8 hours, and        -   (v) not less than 80% in 12 hours;        -   wherein the dissolution profile is determined with a USP            Type 2 apparatus (paddles) at 50 rpm at 37.0±0.5° C. with            500 ml water as the dissolution medium; and    -   wherein said oral pharmaceutical composition provides (i) a Tmax        for amantadine of 11 to 19 hours, and (ii) an AUC_(0-inf) for        amantadine of 44 to 72 ng*hr/ml per mg of said drug, when said        oral pharmaceutical composition is dosed in healthy subjects of        a single dose, human pharmacokinetic study, wherein the subjects        are dosed in the morning after an overnight fast.

Embodiment II-2. The oral pharmaceutical composition of embodiment 11-1,wherein said dissolution profile is (i) 0% to 9% in 2 hours, (ii) 3% to14% in 4 hours, (iii) 24% to 40% in 6 hours, (iv) 45% to 70% in 8 hours,and (v) not less than 82% in 12 hours.

Embodiment II-3. An oral pharmaceutical composition, comprising:

-   -   a drug, wherein the drug is amantadine or a pharmaceutically        acceptable salt thereof, and wherein said oral pharmaceutical        composition comprises from 50 mg to 500 mg of the amantadine or        an equivalent amount of the pharmaceutically acceptable salt        thereof; and    -   at least one excipient that modifies the release of at least a        portion of said drug;    -   wherein said oral pharmaceutical composition has a dissolution        profile of said drug which shows at least four of:        -   (i) not more than 10% dissolution at 2 hours;        -   (ii) 5% to 13% dissolution at 4 hours;        -   (iii) 20% to 43% dissolution at 6 hours;        -   (iv) 50% to 70% dissolution at 8 hours; and        -   (v) at least 80% dissolution at 12 hours;    -   wherein the dissolution profile is determined with a USP Type 2        apparatus (paddles) at 50 rpm at 37.0±0.5° C. with 500 ml water        as the dissolution medium; and    -   wherein said oral pharmaceutical composition provides (i) a Tmax        for amantadine of 11 to 19 hours, and (ii) an AUC_(0-inf) for        amantadine of 44 to 72 ng*hr/ml per mg of said drug, when said        oral pharmaceutical composition is dosed in healthy subjects of        a single dose, human pharmacokinetic study, wherein the subjects        are dosed in the morning after an overnight fast.

Embodiment II-4. An oral pharmaceutical composition, comprising:

-   -   a drug, wherein the drug is amantadine or a pharmaceutically        acceptable salt thereof, and wherein said oral pharmaceutical        composition comprises from 50 mg to 500 mg of the amantadine or        an equivalent amount of the pharmaceutically acceptable salt        thereof; and    -   at least one excipient that modifies the release of at least a        portion of said drug;    -   wherein said oral pharmaceutical composition has a dissolution        profile of said drug which shows at least four of:        -   (i) not more than 9% dissolution at 2 hours,        -   (ii) 3% to 14% dissolution at 4 hours,        -   (iii) 20% to 43% dissolution at 6 hours,        -   (iv) 45% to 70% dissolution at 8 hours; and        -   (v) at least 82% dissolution at 12 hours, using a USP            Apparatus II (Paddles) at 50 rpm with 500 ml water at            37.0±0.5° C. as the dissolution medium;    -   wherein the dissolution profile is determined with a USP Type 2        apparatus (paddles) at 50 rpm at 37.0±0.5° C. with 500 ml water        as the dissolution medium; and    -   wherein said oral pharmaceutical composition provides (i) a Tmax        for amantadine of 11 to 19 hours, and (ii) an AUC_(0-inf) for        amantadine of 44 to 72 ng*hr/ml per mg of said drug, when said        oral pharmaceutical composition is dosed in healthy subjects of        a single dose, human pharmacokinetic study, wherein the subjects        are dosed in the morning after an overnight fast.

Embodiment II-5. The oral pharmaceutical composition of any one ofembodiments II-1 to II-4, wherein the Tmax for amantadine is 12 to 18hours.

Embodiment II-6. The oral pharmaceutical composition of any one ofembodiments II-1 to II-5, wherein the oral pharmaceutical compositionshows each of (i) to (v).

Embodiment II-7. The oral pharmaceutical composition of any one ofembodiments II-1 to II-6, wherein the oral pharmaceutical compositionhas a dissolution of 9% at 4 hours.

Embodiment II-8. The oral pharmaceutical composition of any one ofembodiments II-1 to II-7, wherein the oral pharmaceutical compositionhas a dissolution of 31% at 6 hours.

Embodiment II-9. The oral pharmaceutical composition of any one ofembodiments II-1 to II-8, wherein the oral pharmaceutical compositionhas a dissolution of 61% at 8 hours.

Embodiment II-10. The oral pharmaceutical composition of any one ofembodiments II-1 to II-9, wherein the oral pharmaceutical compositionhas a dissolution of 94% at 12 hours.

Embodiment II-11. An oral pharmaceutical composition, comprising:

-   -   a drug, wherein the drug is amantadine or a pharmaceutically        acceptable salt thereof, and wherein said oral pharmaceutical        composition comprises from 50 mg to 500 mg of the amantadine or        an equivalent amount of the pharmaceutically acceptable salt        thereof; and    -   at least one excipient that modifies the release of at least a        portion of said drug;    -   wherein when dosed to healthy subjects of a single dose, human        pharmacokinetic study, wherein the subjects are dosed in the        morning after an overnight fast, said oral pharmaceutical        composition provides:    -   a Tmax for amantadine of 11 to 19 hours;    -   an AUC_(0-inf) for amantadine of 44 to 72 ng*hr/ml per mg of        said drug; and    -   a pAUC₀₋₈ for amantadine of 1.0 to 2.0 ng*hr/ml per mg of said        drug.

Embodiment II-12. The oral pharmaceutical composition of embodimentII-11, wherein the oral pharmaceutical composition provides a pAUC₀₋₆for amantadine that is 0.3 to 0.9 ng*hr/ml per mg of said drug whendosed to healthy subjects of a single dose, human pharmacokinetic study,wherein the subjects are dosed in the morning after an overnight fast.

Embodiment II-13. An oral pharmaceutical composition, comprising:

-   -   a drug, wherein the drug is amantadine or a pharmaceutically        acceptable salt thereof, and wherein said oral pharmaceutical        composition comprises from 50 mg to 500 mg of the amantadine or        an equivalent amount of the pharmaceutically acceptable salt        thereof; and    -   at least one excipient that modifies the release of at least a        portion of said drug;    -   wherein when dosed to healthy subjects of a single dose, human        pharmacokinetic study, wherein the subjects are dosed in the        morning after an overnight fast, said oral pharmaceutical        composition provides:        -   (i) a fractional AUC from 0 to 4 hours that is less than 1%            of AUC_(0-inf);        -   (ii) a fractional AUC from 0 to 8 hours that is not more            than 4.5% of AUC_(0-inf);        -   (iii) a fractional AUC from 0 to 12 hours that is about 5%            to 15% of AUC_(0-inf);        -   (iv) a fractional AUC from 0 to 18 hours that is about 20%            to 35% of AUC_(0-inf);        -   (v) and a fractional AUC from 0 to 24 hours that is about            34% to 48% of AUC_(0-inf).

Embodiment II-14. The oral pharmaceutical composition of embodimentII-13, wherein the fractional AUC from 0 to 4 is less than 0.2% ofAUC_(0-inf).

Embodiment II-15. The oral pharmaceutical composition of embodimentII-13 or II-14, wherein the fractional AUC from 0 to 8 hours is 1.0% to4.0% of AUC_(0-inf).

Embodiment II-16. The oral pharmaceutical composition of any one ofembodiments II-13 to II-15, wherein the fractional AUC from 0 to 8 hoursis 1.5% to 3.75% of AUC_(0-inf).

Embodiment II-17. The oral pharmaceutical composition of any one ofembodiments II-13 to II-16, wherein the fractional AUC from 0 to 8 hoursis 1.75% to 3.5% of AUC_(0-inf).

Embodiment II-18. The oral pharmaceutical composition of any one ofembodiments II-13 to II-17, wherein the fractional AUC from 0 to 12hours that is about 7.0% to 12.0% of AUC_(0-inf).

Embodiment II-19. The oral pharmaceutical composition of any one ofembodiments II-13 to 11-18, wherein the fractional AUC from 0 to 18hours is about 22.5% to 27.5% of AUC_(0-inf).

Embodiment II-20. An oral pharmaceutical composition, comprising:

-   -   a drug, wherein the drug is amantadine or a pharmaceutically        acceptable salt thereof, and wherein said oral pharmaceutical        composition comprises from 50 mg to 500 mg of the amantadine or        an equivalent amount of the pharmaceutically acceptable salt        thereof; and    -   at least one excipient that modifies the release of at least a        portion of said drug;    -   wherein when dosed to healthy subjects of a single dose, human        pharmacokinetic study, wherein the subjects are dosed in the        morning after an overnight fast, said oral pharmaceutical        composition provides:    -   a fractional AUC from 0 to 4 hours that is less than 0.25% of        AUC_(0-inf);    -   a fractional AUC from 0 to 8 hours that is less than 3.5% of        AUC_(0-inf);    -   a fractional AUC from 0 to 12 hours that is about 5 to 12% of        AUC_(0-inf); and    -   a fractional AUC from 0 to 18 hours that is about 25 to 60% of        AUC_(0-inf).

Embodiment II-21. The oral pharmaceutical composition of any one ofembodiments II-1 to II-20, comprising from 100 mg to 450 mg ofamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

Embodiment II-22. The oral pharmaceutical composition of any one ofembodiments II-1 to II-21, comprising from 120 mg to 150 mg ofamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

Embodiment II-23. The oral pharmaceutical composition of any one ofembodiments II-1 to II-22, comprising 137 mg of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof.

Embodiment II-24. The oral pharmaceutical composition of any one ofembodiments II-1 to II-21, comprising from 260 mg to 305 mg ofamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

Embodiment II-25. The oral pharmaceutical composition of any one ofembodiments II-1 to II-21, or II-24, comprising 274 mg of amantadine, oran equivalent amount of a pharmaceutically acceptable salt thereof.

Embodiment II-26. The oral pharmaceutical composition of any one ofembodiments II-1 to II-25, comprising one, two, three, or four unitdosage forms.

Embodiment II-27. The oral pharmaceutical composition of any one ofembodiments II-1 to II-26, comprising one or two unit dosage forms.

Embodiment II-28. The oral pharmaceutical composition of any one ofembodiments II-1 to II-27, wherein the drug is a pharmaceuticallyacceptable salt of amantadine.

Embodiment II-29. The oral pharmaceutical composition of any one ofembodiments II-1 to II-28, wherein the drug is amantadine hydrochloride.

Embodiment II-30. The oral pharmaceutical composition of any one ofembodiments II-1 to II-29, comprising less than 6000 ppm of organicsolvent.

Embodiment II-31. The oral pharmaceutical composition of any one ofembodiments II-1 to II-30, comprising less than 2000 ppm of organicsolvent.

Embodiment II-32. The oral pharmaceutical composition of any one ofembodiments II-1 to II-31, comprising:

-   -   a plurality of coated core seeds, wherein each coated core seed        comprises:        -   a core seed;        -   a drug coating surrounding the core seed, wherein the drug            coating comprises amantadine or a pharmaceutically            acceptable salt thereof and one or more pharmaceutically            acceptable excipients;        -   an extended release coating surrounding the drug coating,            wherein the extended release coating comprises one or more            release modifying excipients; and    -   a capsule shell, wherein the plurality of coated core seeds is        encapsulated within the capsule shell.

Embodiment II-33. The oral pharmaceutical composition of embodimentII-32, wherein the plurality of coated core seeds comprises less than6000 ppm organic solvent.

Embodiment II-34. The oral pharmaceutical composition of embodimentII-32, wherein the plurality of coated core seeds comprises less than2000 ppm organic solvent.

Embodiment II-35. A method of reducing levodopa-induced dyskinesia (LID)in a subject with Parkinson's disease in need thereof, comprising orallyadministering once daily to the subject an oral pharmaceuticalcomposition according to any one of embodiments II-1 to II-34, whereinLID is reduced in the subject.

Embodiment II-36. The method of embodiment II-35, wherein reducing LIDcomprises reducing the severity of dyskinesia.

Embodiment II-37. The method of embodiment II-35 or II-36, wherein thereduction of LID is evaluated with the Unified Dyskinesia Rating Scale(UDysRS).

Embodiment II-38. A method of increasing ON time without troublesomedyskinesia in a subject with Parkinson's disease in need thereof,wherein the subject has levodopa-induced dyskinesia (LID), the methodcomprising orally administering once daily to the subject an oralpharmaceutical composition according to any one of embodiments II-1 toII-34.

Embodiment II-39. The method of embodiment II-38, wherein the increasein ON time without troublesome dyskinesia is determined in a placebocontrolled, double blind clinical study.

Embodiment II-40. A method of reducing OFF time in a subject withParkinson's disease in need thereof, wherein the subject haslevodopa-induced dyskinesia (LID), the method comprising orallyadministering once daily to the subject an oral pharmaceuticalcomposition according to any one of embodiments II-1 to II-34, whereinOFF time is reduced in the subject.

Embodiment II-41. The method of embodiment II-40, wherein the increasein OFF time is determined in a placebo controlled, double blind clinicalstudy.

Embodiment II-42. A method of treating a hypokinetic disorder in asubject with Multiple Sclerosis in need thereof, comprising orallyadministering once daily to the subject an oral pharmaceuticalcomposition according to any one of embodiments II-1 to II-34.

Embodiment II-43. The method of embodiment II-42, wherein thehypokinetic disorder is walking impairment.

Embodiment II-44. The method of any one of embodiments II-35 to II-43,wherein the oral pharmaceutical composition is administered to thesubject once nightly.

Embodiment II-45. The method of any one of embodiments II-35 to II-44,wherein the oral pharmaceutical composition is administered to thesubject 0 to 4 hours before bedtime.

Embodiment II-46. The method of any one of embodiments II-35 to II-45,wherein the daily dose administered to the subject is 100 mg to 450 mgof amantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

Embodiment II-47. The method of any one of embodiments II-35 to II-46,wherein the once daily dose administered to the subject is 120 mg to 150mg of amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof.

Embodiment II-48. The method of any one of embodiments II-35 to II-47,wherein the once daily dose administered to the subject is 137 mg ofamantadine, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

Embodiment II-49. The method of any one of embodiments II-35 to II-46,wherein the once daily dose administered to the subject is 260 mg to 305mg of amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof.

Embodiment II-50. The method of any one of embodiments II-35 to II-46,or II-49, wherein the once daily dose administered to the subject is 274mg of amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof.

Embodiment II-51. The method of any one of embodiments II-35 to II-50,wherein the oral pharmaceutical composition is administered as one, two,three, or four unit dosage forms.

Embodiment II-52. The method of any one of embodiments II-35 to II-51,wherein the oral pharmaceutical composition is administered as one ortwo unit dosage forms.

Embodiment II-53. The method of any one of embodiments II-35 to II-52,wherein the oral pharmaceutical composition is administered as two orthree unit dosage forms each comprising 68.5 to 175 mg amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof.

Embodiment II-54. The method of any one of embodiments II-35 to II-52,wherein the drug is a pharmaceutically acceptable salt of amantadine.

Embodiment II-55. The method of any one of embodiments II-35 to II-53,wherein the drug is amantadine hydrochloride.

Embodiment II-56. An oral pharmaceutical composition according to anyone of embodiments II-1 to II-34 for use in a method of reducinglevodopa-induced dyskinesia (LID) in a subject with Parkinson's diseasein need thereof, wherein the method comprises orally administering oncedaily to the subject the oral pharmaceutical composition.

Embodiment II-57. The oral pharmaceutical composition for use ofembodiment II-56, wherein reducing LID comprises reducing the severityof dyskinesia.

Embodiment II-58. The oral pharmaceutical composition for use ofembodiment II-56 or II-57, wherein the reduction of LID is evaluatedwith the Unified Dyskinesia Rating Scale (UDysRS).

Embodiment II-59. An oral pharmaceutical composition according to anyone of embodiments II-1 to II-34 for use in a method of increasing ONtime without troublesome dyskinesia in a subject with Parkinson'sdisease in need thereof, wherein the subject has levodopa-induceddyskinesia (LID), the method comprising orally administering once dailyto the subject the oral pharmaceutical composition.

Embodiment II-60. The oral pharmaceutical composition for use ofembodiment II-59, wherein the increase in ON time without troublesomedyskinesia is determined in a placebo controlled, double blind clinicalstudy.

Embodiment II-61. An oral pharmaceutical composition according to anyone of embodiments II-1 to II-34 for use in a method of reducing OFFtime in a subject with Parkinson's disease in need thereof, wherein thesubject has levodopa-induced dyskinesia (LID), the method comprisingorally administering once daily to the subject the oral pharmaceuticalcomposition.

Embodiment II-62. The oral pharmaceutical composition for use ofembodiment II-61, wherein the increase in OFF time is determined in aplacebo controlled, double blind clinical study.

Embodiment II-63. An oral pharmaceutical composition according to anyone of embodiments II-1 to II-34 for use in a method of treating ahypokinetic disorder in a subject with Multiple Sclerosis in needthereof, the method comprising orally administering once daily to thesubject the oral pharmaceutical composition.

Embodiment II-64. The oral pharmaceutical composition for use ofembodiment II-63, wherein the hypokinetic disorder is walkingimpairment.

Embodiment II-65. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-64, wherein the oral pharmaceuticalcomposition is administered to the subject once nightly.

Embodiment II-66. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-65, wherein the oral pharmaceuticalcomposition is administered to the subject 0 to 4 hours before bedtime.

Embodiment II-67. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-66, wherein the daily dose administered tothe subject is 100 mg to 450 mg of amantadine, or an equivalent amountof a pharmaceutically acceptable salt thereof.

Embodiment II-68. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-67, wherein the once daily dose administeredto the subject is 120 mg to 150 mg of amantadine, or an equivalentamount of a pharmaceutically acceptable salt thereof.

Embodiment II-69. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-68, wherein the once daily dose administeredto the subject is 137 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof.

Embodiment II-70. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-67, wherein the once daily dose administeredto the subject is 260 mg to 305 mg of amantadine, or an equivalentamount of a pharmaceutically acceptable salt thereof.

Embodiment II-71. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-67, or II-70, wherein the once daily doseadministered to the subject is 274 mg of amantadine, or an equivalentamount of a pharmaceutically acceptable salt thereof.

Embodiment II-72. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-71, wherein the oral pharmaceuticalcomposition is administered as one, two, three, or four unit dosageforms.

Embodiment II-73. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-72, wherein the oral pharmaceuticalcomposition is administered as one or two unit dosage forms.

Embodiment II-74. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-73, wherein the oral pharmaceuticalcomposition is administered as two or three unit dosage forms eachcomprising 68.5 to 175 mg amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof.

Embodiment II-75. The oral pharmaceutical composition for use of any oneof claims 56 to 74, wherein the drug is a pharmaceutically acceptablesalt of amantadine.

Embodiment II-76. The oral pharmaceutical composition for use of any oneof embodiments II-56 to II-75, wherein the drug is amantadinehydrochloride.

EXAMPLES

The present disclosure may be better understood by reference to thefollowing examples, which are illustrative and not intended to limit thescope of the disclosure in any way.

Example 1: Amantadine Extended Release Coated Pellet Formulation of TypeC

Amantadine HCl extended release coated pellet compositions designed fororal administration were prepared using the components and relativeamounts shown in Table 1 below.

The drug coating dispersion was prepared by adding HPMC 5 cps andCopovidone to isopropyl alcohol with continuous stirring. Purified waterwas added to this dispersion and stirring continued until a clearsolution is formed. Drug (Amantadine HCl) was then added to this clearsolution and stirring continued until the drug was completely dissolved.Finally, talc was added and dispersed uniformly by stirring.

The seed pellets, Celphere beads (screen sizes #35 to #50 i.e., 300 to500 micron), were loaded in a Wurster coating unit. The drug coatingdispersion was sprayed onto the seed pellets to the desired increase incoat weight, providing a drug coating of amantadine and excipients onthe seed pellets, followed by a period of drying to remove residualorganic solvent and water in the drug coated pellets. The resulting drugcoated pellets were sieved to retain the fraction between screens #18and #24 (approximately 700 μm to 1 mm diameter).

The seal coating dispersion was prepared by adding HPMC 5 cps toisopropyl alcohol with continuous stirring. Purified water was added tothis dispersion and stirring continued until a clear solution wasformed. Talc was added and dispersed uniformly by stirring. The sieveddrug coated pellets were loaded in a Wurster coating unit. The sealcoating dispersion was sprayed over the drug coated pellets followed bya period of drying to remove residual organic solvent and water in thepellets. The resulting seal coated pellets were sieved to retain thefraction between screens #18 and #24.

The ER coating solution was prepared by dissolving ethyl cellulose(viscosity 7 cps) in isopropyl alcohol and purified water and stirringuntil a clear solution was formed. Povidone K-90 was then dissolved inthis clear solution followed by addition of plasticizer Miglyol 812Nwith continuous stirring to form a clear solution. The sieved sealcoated pellets were loaded in a Wurster coating unit. The ER coatingsolution was sprayed over the seal coated pellets followed by a periodof drying to affect the ER coat and remove residual organic solvent andwater in the pellets. After drying, magnesium stearate was spread on thetop bed of the coated pellets in the annulus region followed byrecirculation of the pellets in the Wurster unit to blend the magnesiumstearate with the coated pellets. The resulting ER coated pellets weresieved to retain the fraction between screens #18 and #24.

The ER coated pellets containing the unit dose of amantadinehydrochloride were filled into empty hard gelatin capsule shells usingan encapsulator equipped with pellet dosing chamber. For 48.4 mgamantadine (60 mg amantadine HCl) and 112.8 mg amantadine (140 mgamantadine HCl) size 1 capsule shells were used. The 48.4 mg capsuleshad a water content of 2.0% by Karl Fischer and a residual isopropylalcohol level of 6464 ppm; the 112.8 mg capsules had a water content of1.8% by Karl Fischer and a residual isopropyl alcohol level of 6709 ppm.

TABLE 1 Composition of Type C amantadine HCl ER capsules combined w/wComponent Function of capsule Seed Pellet Microcrystalline celluloseCore seeds 12.54%  spheres (Celphere ®), NF Drug Coating DispersionAmantadine Hydrochloride, USP Active 43.89%  Hydroxypropyl methylcellulose, Binder 11.70%  5 cps, USP Copovidone, NF Binder 2.92% Talc,NF Anti-tack 2.19% Isopropyl alcohol, USP Solvent Trace¹  PurifiedWater, USP Solvent Trace¹  Seal Coating Dispersion Hydroxypropyl methylcellulose, Coating polymer 6.66% 5 cps, USP Talc, NF Anti-tack 0.67%Isopropyl alcohol, USP Solvent Trace¹  Purified Water, USP SolventTrace¹  Extended Release Coating Ethyl cellulose, 7 cps, NF Coatingpolymer 15.39%  Povidone K-90, USP Pore former 2.08% Medium chaintriglycerides Plasticizer 1.86% (Miglyol 812N), NF Isopropyl alcohol,USP Solvent Trace¹  Purified Water, USP Solvent Trace¹  LubricantMagnesium Stearate NF Lubricant 0.10% Notes: USP,—United StatesPharmacopeia, NF = National Formulary, All ingredient quantities are %w/w ¹Purified water and isopropyl alcohol are removed during processing.

Example 2: Amantadine Extended Release Coated Pellet Formulation of TypeD

Amantadine HCl extended release coated pellet compositions designed fororal administration were prepared using the components and relativeamounts shown in Table 2 below.

The drug coating dispersion was prepared by combining the coatingdispersion components of Table 2 in purified water without an organicsolvent.

The seed pellets, Celphere beads (screen sizes #35 to #50 i.e., 300 to500 micron), were loaded in a Wurster coating unit. The drug coatingdispersion was sprayed onto the seed pellets to the desired increase incoat weight, providing a drug coating of amantadine and excipients onthe seed pellets, followed by a period of drying to remove residualwater. The resulting drug coated pellets were sieved to retain thefraction between screens #18 and #24 (approximately 700 μm to 1 mmdiameter).

The seal coating dispersion was prepared by combining the components ofthe seal coating dispersion of Table 2 in purified water without organicsolvent. The sieved drug coated pellets were loaded in a Wurster coatingunit. The seal coating dispersion was sprayed over the drug coatedpellets followed by a period of drying to remove residual water in thepellets. The resulting seal coated pellets were sieved to retain thefraction between screens #18 and #24.

The ER coating solution was prepared by dissolving ethyl cellulose(viscosity 7 cps) in isopropyl alcohol and purified water and stirringuntil a clear solution was formed. Povidone K-90 was then dissolved inthis clear solution followed by addition of plasticizer Miglyol 812Nwith continuous stirring to form a clear solution. The sieved sealcoated pellets were loaded in a Wurster coating unit. The ER coatingsolution was sprayed over the seal coated pellets followed by a periodof drying to affect the ER coat and remove residual organic solvent andwater in the pellets. After drying, magnesium stearate was spread on thetop bed of the coated pellets in the annulus region followed byrecirculation of the pellets in the Wurster unit to blend the magnesiumstearate with the coated pellets. The resulting ER coated pellets weresieved to retain the fraction between screens #18 and #24.

The ER coated pellets containing the unit dose of amantadinehydrochloride were filled into empty hard gelatin capsule shells usingan encapsulator equipped with pellet dosing chamber. For 68.5 mgamantadine (85 mg amantadine HCl), size 2 capsule shells were used. For137 mg amantadine (170 mg amantadine HCl), size 0 capsule shells wereused. The capsules had a water content of 2% by Karl Fischer and aresidual isopropyl alcohol level of 1051 ppm.

TABLE 2 Composition of Type D amantadine HCl ER capsules combined w/wComponent Function of capsule Seed Pellet Microcrystalline celluloseCore seeds 12.44%  spheres (Celphere ®), NF Drug Coating DispersionAmantadine Hydrochloride, USP Active 43.54%  Hydroxypropyl methylcellulose, Binder 11.61%  USP Copovidone, NF Binder 2.90% Talc, NFAnti-tack 2.17% Purified Water, USP Solvent Trace¹  Seal CoatingDispersion Hydroxypropyl methyl cellulose, Coating polymer 6.60% USPTalc, NF Anti-tack 0.66% Purified Water, USP Solvent Trace¹  ExtendedRelease Coating Ethyl cellulose, 7 cps, NF Coating polymer 15.91% Povidone K-90, USP Pore former 2.15% Medium chain triglyceridesPlasticizer 1.92% (Miglyol 812N), NF Isopropyl alcohol, USP SolventTrace¹  Purified Water, USP Solvent Trace¹  Lubricant MagnesiumStearate, NF Lubricant 0.10% Notes: USP,—United States Pharmacopeia, NF= National Formulary, All ingredient quantities are % w/w ¹Purifiedwater and isopropyl alcohol are removed during processing.

Example 3: Dissolution of Amantadine Extended Release Coated PelletFormulations

Dissolution of the capsules of Examples 1 and 2 were performed using aUSP Apparatus II (Paddles) at 50 rpm with 500 ml water at 37.0±0.5° C.as the dissolution medium. The mean results are shown in Table 3 belowand FIG. 1.

The in vitro dissolution shows a decreased release of amantadine fromthe compositions over the first 4, 6 and 8 hours.

TABLE 3 Dissolution profiles Percent Released Time (hr) Type C (Ex. 1)Type D (Ex. 2) 2  2 1 4 18 9 6 44 31 8 68 61 10 83 82 12 93 94 16 N/A102

Example 4: Pharmacokinetic Study of Two Amantadine ER Coated PelletFormulations

Objective: The primary objective of the study was to evaluate thepharmacokinetic profiles of the two formulations of ER amantadine HCl ofExamples 1 and 2. The secondary objective was to evaluate the safety andtolerability of a single 340 mg dose of the two formulations of ERamantadine HCl of Examples 1 and 2.

Study design: This was a Phase 1, randomized, single dose, open-label,two-period, two-treatment crossover, fasting pharmacokinetic study inwhich single 340 mg doses of formulations of Example 1 (Type C) andExample 2 (Type D) Amantadine ER capsules, i.e. study drugs, werecompared to each other. The study included 42 healthy subjects who wererandomly assigned in a 1:1 ratio to 1 of 2 treatment sequences (TypeC->Type D or Type D->Type C). For type C, 340 mg amantadinehydrochloride consisted of two 140 mg capsules and one 60 mg capsule.For type D, 340 mg amantadine hydrochloride consisted of two 170 mgcapsules.

Methods: Subjects were screened for inclusion and exclusion criteriawithin 21 days of study screening. On the day prior to the first periodof dosing, subjects were admitted to the unit and remained there untilafter the 48 hour blood sample was taken. In each study period, subjectswere dosed on the day after checking into the unit and discharged afterthe 48 hour post-dose blood sample was taken. Subjects returned to theunit for subsequent blood draws (72 hours and 96 hours). There was a 7to 14 day washout period between the first and second dose. Safetymonitoring was conducted during and after administration of each studydrug.

For each study period, after an overnight fast, the study drug wasadministered to the subjects while in a sitting position with 240 mL ofwater. Subjects were required to remain in a sitting position for atleast 2 hours after administration. No food was permitted until 4 hoursafter administration of study drug. Blood samples were collected at 0(pre-dose), 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 15, 16, 18, 20, 24, 30,36, 48, 72 and 96 hours following each dose. Plasma samples were assayedfor amantadine by a validated liquid chromatography/tandem massspectroscopy (LC/MS/MS) method. Pharmacokinetic parameters werecalculated using a non-compartmental analysis with WinNonlin software(version 6.2.1; Pharsight Corporation).

Adverse events were monitored throughout the study. Vital signs (pulserate, blood pressure and body temperature), clinical laboratory measures(biochemistry, hematology, and urinalysis) and ECGs were collected atvarious times during the study.

Results: A total of 42 subjects comprising healthy male and femaleadults were screened and randomly assigned to the treatment armsdescribed above, and 39 subjects completed the study. All 42 subjectswere included in the safety population and 39 subjects were included inthe primary analysis population.

The pharmacokinetic results from this study shown in Table 4 below andFIG. 2 demonstrate that these formulations provide similar Cmax, Tmax,AUC_(0-inf), AUC₀₋₂₄ and t_(1/2).

TABLE 4 Pharmacokinetic data for single dose PK study (Mean ± SD exceptas noted) Parameter Type C (n = 39) Type D (n = 39) AUC_(0-inf)(ng*hr/ml) 22687.6 ± 7747.79  22442.2 ± 8291.63  AUC₀₋₂₄ (ng*hr/ml)9805.6 ± 2361.02 9111.0 ± 2236.41 Cmax (ng/ml) 670.9 ± 180.76 660.2 ±183.05 Tmax (hr)^(a) 15.0 [12.0, 24.02] 16.0 [12.0, 30.13] t_(1/2) (hr)13.614 ± 3.1252  13.752 ± 3.6535  ^(a): Tmax is the median value datawithin square brackets are min and max values.

From partial AUC values for the two formulations over the first 4, 6, 8,10, 12, 14 and 16 hours, the exposure in the early hours afteradministration for type D compositions is less than for the Type Ccomposition, see Table 5 below. This is also shown in FIG. 3.

TABLE 5 pAUC values (ng * hr/ml per mg amantadine HCl) for single dosePK study Time (hr) Type C Type D 4 0.15 0.11 6 1.04 0.67 8 2.85 1.93 105.31 3.89 12 8.27 6.49 14 11.71 9.67 16 15.43 13.23 18 18.98 16.77

Safety results: within the 42 subjects randomized to the study, adverseevents were recorded and coded using MedDRA Version 17.0. The number andpercentage of the population reporting at least one adverse event withinthe system organ class are shown in Table 6 below. The gastrointestinaldisorder frequencies for the Type C and Type D compositions werecompared with a logistic models fit using generalized estimatingequations (GEE, Exchangeable Correlation Structure). The analysisprovided an odds ratio of 3.407 and a p-value of 0.0685, indicating thatthe odds of a gastrointestinal adverse event is 3.4 times greater forthe Type C formulation than for the Type D formulation.

TABLE 6 Adverse events observed Number (%) of subjects with AdverseEvents MedDRA System Organ Class Type C (n = 40) Type D (n = 41)Subjects with at least 1 AE  7 (17.5%) 3 (7.3%) Gastrointestinaldisorders  4 (10.0%) 1 (2.4%) Nervous system disorders 1 (2.5%) 1 (2.4%)General disorders and 0 1 (2.4%) administration site conditionsInfections and infestations 1 (2.5%) 0 Injury, poisoning and 1 (2.5%) 0procedural complications Metabolism and nutrition 0 1 (2.4%) disordersPsychiatric disorders 1 (2.5%) 1 (2.4%)

Example 5: Statistical Analysis of GI Adverse Events Across MultipleStudies

Objective: to compare the incidence of gastrointestinal adverse eventsfrom single dose, fasting human pharmacokinetic studies for Type C andType D formulations.

This post hoc analysis combined the gastrointestinal adverse events(based on MedDRA coding) across 5 single dose, fasting humanpharmacokinetic studies to determine if the gastrointestinal adverseevent difference observed in Example 4 is statistically significant. Forstudies with treatments other than Type C or Type D formulations, onlythe Type C and Type D arms were included. Furthermore, only single dose,fasting arms were included. Combining the results provided both agreater number of subjects and a greater number of adverse events. Thestudies included are detailed in Table 7 below. Statistical analysis ofthe data was performed using a logistic models fit using generalizedestimating equations (GEE, Exchangeable Correlation Structure).

TABLE 7 Number of subjects and number of GI adverse events in studiesfor analysis Type C Type D Study Description, dose of amantadine HCl NGI AEs N GI AEs A: formulation selection study, 100 mg 18 5 — — B: doseproportionality study, 85/170/340 mg^(a) — — 30 1 C: bioequivalencestudy, 340 mg 40 4 41 1 D: food effect study, 170 mg (fasted only) — —36 0 E: bioequivalence study, 170 mg^(b) — — 21 0 ^(a): this studycompared three strengths of one Type D formulation, the GI AE observedwas at the lowest strength ^(b): two preparations of Type D formulations

The studies included 147 different subjects and statistical results forthe gastrointestinal adverse effects in the pooled data showed an oddsratio for Type C vs. Type D of 16.247 and a p-value of <0.0001. Thesmaller p-value as compared to the previous example may be partiallyexplained by the increase in sample size and partially explained by theincrease in magnitude of the effect (9 of 58 for Type C vs 2 of 128 forType D).

Example 6: A Randomized, Double-Blind, Placebo-Controlled Study of theEfficacy and Safety of Amantadine Extended Release Oral Capsules for theTreatment of Levodopa-Induced Dyskinesia in Parkinson's Disease

This study was performed using a formulation of amantadine hydrochlorideprepared according the processes of Example 1 above, for Type C. StudyObjectives: This study was designed to evaluate the efficacy of threedose levels of Amantadine Extended Release (ER) oral capsules dosed oncenightly at nighttime for the treatment of levodopa-induced dyskinesia(LID) in subjects with Parkinson's Disease (PD). In addition, the studywas designed to demonstrate the safety and tolerability of Amantadine ERoral capsules dosed once nightly for the treatment of LID in subjectswith PD. Study design: This was a multi-center, randomized,double-blind, placebo-controlled, 4-arm parallel group study ofAmantadine ER in subjects with PD who have LID. Consenting subjects whomet eligibility criteria were randomized 1:1:1:1 to receive one of thefollowing 4 treatments, each administered as once nightly, dosed atnight:

-   -   Treatment A: Placebo,    -   Treatment B: 260 mg Amantadine ER (ADS-5102) (prepared according        the process of Example 1 for Type C),    -   Treatment C: 340 mg Amantadine ER (ADS-5102) (prepared according        the process of Example 1 for Type C)    -   Treatment D: 420 mg Amantadine ER (ADS-5102) (prepared according        the process of Example 1 for Type C)

Subjects who were randomized to Treatment C received, in double-blindfashion, 260 mg Amantadine ER once nightly during week 1, with anincrease to 340 mg once nightly at the beginning of week 2. Subjects whowere randomized to Treatment D, in double-blind fashion, 260 mgAmantadine ER once nightly during week 1, with an increase to 340 mgAmantadine ER once nightly during week 2, with a further increase to 420mg once nightly at the beginning of week 3. Dosing for all groupscontinued at the nominal dose through week 8.

Following completion of the baseline visit and randomization, subjectsreturned to the clinic after 1, 2, 4, 6, and 8 weeks of dosing, with afollow-up visit 14 days following the last dose of study drug. Studyvisits and assessments were scheduled during the hours between 10 amthrough 4 pm. A set of two 24-hour diaries were be completed during 48hours prior to randomization and 48 hours prior to selected studyvisits. The diary was used to score five different conditions in30-minute intervals: Sleep, OFF, ON without dyskinesias, ON withnontroublesome dyskinesias, ON with troublesome dyskinesias.

Blood samples were collected at selected study visits for determinationof amantadine plasma concentrations, and evaluation of steady-statepopulation pharmacokinetics. Subject participation during the study wasup to 12 weeks including a 2-week (maximum) screening period, 8-week(maximum) treatment period, and a 2-week follow-up period. Subjectsunable to tolerate their assigned study drug assignment permanentlydiscontinued study drug and continued to be followed for safety through2 weeks following the last dose of study drug.

Patient Eligibility Criteria: Subjects were eligible to take part in thestudy if they met the inclusion and did not meet the exclusion criteria.Selected key criteria were as follows:

Inclusion Criteria:

-   -   Male or female adults    -   Between 30 and 85 years of age, inclusive    -   Ambulatory or ambulatory-aided (e.g. walker or cane) ability        while ON, such that the subject can could complete study        assessments    -   Knowledgeable and reliable caregiver/study partner, if        appropriate, to accompany the subject to study visits and assist        in completion of study instruments, as needed and allowed    -   Signed a current IRB/IEC-approved informed consent form    -   Following diary training, the subject was willing and able to        understand and complete the 24-hour PD home diary        (caregiver/study partner assistance allowed)    -   Parkinson's Disease, complicated per UK Parkinson's Disease        Society (UKPDS) Brain Bank Clinical Diagnostic Criteria    -   On a stable regimen of antiparkinson's medications, including        levodopa, for at least 30 days prior to screening, with any        levodopa administered not less than three times daily, and        willing to continue the same doses and regimens during study        participation    -   A score of at least 2 on part IV, item 4.2 (functional impact of        dyskinesias) of the Unified Parkinson's Disease Rating Scale        (MDS-UPDRS), at screening and at Day 1 (baseline)    -   Using the 48-hour PD home diaries completed just prior to Day 1        (baseline), at least 2 half-hour time periods between 10 am and        4 pm of each 24-hour period are indicated as “ON with        troublesome dyskinesia”

Key Exclusion Criteria:

-   -   History of deep brain simulation; history of exclusively        diphasic, off state, myoclonic or akathetic dyskinesia without        peak dose dyskinesia    -   History of other neurological disease that, in the opinion of        the investigator, would affect cognition or motor function,        including, but not limited to Alzheimer's dementia, Huntington's        disease, Lewy body dementia, frontotemporal dementia,        corticobasal degeneration, progressive supranuclear palsy,        multiple system atrophy, motor or sensory dysfunction secondary        to stroke or brain trauma, or multi-infarct dementia with        lacunae.    -   Presence of cognitive impairment, as evidenced by a Mini-mental        State Examination (MMSE) score of less than 24 during screening.    -   Presence of an acute or chronic major psychiatric disorder        (e.g., Major Depressive Disorder) or symptom (e.g.,        hallucinations, agitation, paranoia) that, in the opinion of the        investigator, would affect the subject's ability to complete        study assessments    -   History of sensory impairments (e.g., hearing, vision) that, in        the opinion of the investigator, would impair the subject's        ability to complete study assessments    -   History of alcohol or drug dependence or abuse within 2 years        prior to screening    -   History of seizures within 2 years prior to screening    -   History of stroke or TIA within 2 years prior to screening    -   History of myocardial infarction, or NYHA Functional        Classification of Heart Failure Class 3 or 4 within 2 years        prior to screening    -   History of cancer within 5 years prior to screening, with the        following exceptions: adequately treated non-melanomatous skin        cancers, localized bladder cancer, non-metastatic prostate        cancer or in situ cervical cancer    -   Any of the following laboratory test results at screening:        Hemoglobin<10 g/dL, WBC<3.0×10⁹/L, Neutrophils<1.5×10⁹/L,        Lymphocytes<0.5×10⁹/L, Platelets<100×10⁹/L, Hemoglobin A1C>9%,        or Aspartate aminotransferase (AST) and/or alanine        aminotransferase (ALT)>2 times the upper limit of normal    -   Estimated GFR<50 mL/min/1.73 m² by Modification of Diet in Renal        Disease (MDRD) equation    -   Any clinically significant ECG abnormalities, including any        findings of abnormal ventricular conduction of rhythm other than        isolated PVCs or first degree AV block    -   Inability to swallow oral capsules, or a history of        gastrointestinal malabsorption that would preclude the use of        oral medication

Study Endpoints: The primary efficacy endpoint is the change frombaseline to week 8 in the Unified Dyskinesia Rating Scale (UDysRS) totalscore. Key secondary endpoints include change from baseline to week 8:

-   -   Total Objective Score (III, IV) of the UDysRS    -   ON time without troublesome dyskinesia (ON without dyskinesia        plus ON with non-troublesome dyskinesia), based on the PD home        diary    -   ON time with troublesome dyskinesia, based on a standardized PD        home diary    -   Total ON time with dyskinesia (non-troublesome and troublesome)    -   Total OFF time    -   Unified Parkinson's Disease Rating Scale (MDS-UPDRS), combined        score (Parts I, II and III)    -   Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part IV,        items 4.1 (time spent with dyskinesias) and 4.2 (functional        impact of dyskinesias)    -   Unified Parkinson's Disease Rating Scale (MDS-UPDRS), individual        part scores (I, II, III, and IV)    -   Clinician's Global Impression of Change in overall PD symptoms,        determined by a question completed by the investigator    -   Health-related Quality of Life as measured by a PD-specific        HRQoL instrument, the PDQ-39    -   Fatigue as measured by the Fatigue Severity Scale (FSS). This        scale includes 9 questions that are completed by the patient        using a rating scale from 1 (strongly disagree) to 7 (strongly        agree). Safety, including adverse events, safety-related study        drug discontinuations, vital signs, and laboratory tests.

The following mixture of traditional and new scales have been selectedfor this study:

-   -   Unified Dyskinesia Rating Scale (UDysRS) was used for primary        outcome measure. This scale has four parts, and a total possible        score of 104:

-   I: Historical Disability (patient perceptions) of On-Dyskinesia    impact

-   II: Historical Disability (patient perceptions) of Off-Dystonia    impact

-   III: Objective Impairment (dyskinesia severity, anatomic    distribution, and type, based on 4 observed activities)

-   IV: Objective Disability based on Part III activities    -   ON time without troublesome dyskinesia, based on a standardized        Parkinson's disease home diary.    -   MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part        IV, items 4.1 (duration of dyskinesias: 0=none, 4=76-100% of the        waking day) and 4.2 (disability of dyskinesias: 0=not disabling,        4=completely disabling) was a secondary outcome measure.

Statistical Methods

Efficacy Analyses: The efficacy analysis population included allrandomized and dosed subjects who provided at least one post-baselineefficacy assessment, and met prespecified entry criteria. Unlessspecified otherwise, all efficacy endpoints were analyzed using analysisof covariance (ANCOVA) models with the change from baseline to Week 8 asthe dependent variable, treatment group as a factor, and the baselinevalue of the corresponding endpoint as a covariate. These models will beused for both pair-wise comparisons between each amantadine ER dosegroup versus placebo and for testing for a linear dose-responserelationship. The dose-response test will be carried out using thescores 0, 260, 340, and 420 and additionally using equally spaced scoresfor the treatment groups. For the efficacy endpoint of UDysRS score, theprimary analysis compared the 340 mg amantadine ER group to the placebogroup using a two-sided test at the 5% level of significance.

The secondary endpoints were analyzed using the same types of ANCOVAmodels as described for the primary endpoint, except for CGIC which wasa CMH analysis. All secondary comparisons between treatment groups wereperformed using two-sided tests at the 5% level of significance. A lastobservation carried forward (LOCF) approach was utilized for missingdata. The primary efficacy analysis was repeated for the per-protocolpopulation, a subset of the efficacy analysis population who providedweek 8 efficacy assessments. The CGI was a CMH analysis.

-   -   Results: selected study results are shown in the table below.

TABLE 8 Mean values and LS Mean changes (by Group) Instruments Placebo260 mg 340 mg 420 mg Effect Unified Dyskinesia 39.2  40.2  44.1  41.2 Baseline Reduction in total UDysRS Rating Scale −6.7  −12.3  −17.9 −16.7  LS change greater for the treatment (UDysRS) — −14%  −25% −24% (Active- groups than placebo total score Placebo)/ Baseline UnifiedDyskinesia 13.5  16.7  18.7  15.8  Baseline Reduction in UDysRS totalRating Scale −1.9  −4.4  −7.1  −8.3  LS change Objective greater for the(UDysRS) — −15%  −28% −41%  (A-P)/base treatment groups than placeboobjective total (parts III, IV) Unified Parkinson’s 11.7  10.6  11.8 10.5  Baseline Reduction in MDS-UPDRS Disease Rating Scale −1.5  −2.2 −3.9  −4.9  LS change Part IV greater for the (UPDRS, MDS — −6.6%  −20%−32%  (A-P)/base treatment groups than placebo revision), Part IV ONtime without 6.9 6.6 7.7 9.0 Baseline Increase in ON time withouttroublesome 0.9 4.1 3.8 3.6 LS change troublesome dyskinesia for thedyskinesia (hours) — 48%  38% 30% (A-P)/base treatment groups versusplacebo ON time with 10.2  10.0  8.0 10.4  Baseline Decrease in ON timewith dyskinesia (hours) −1.9  −3.0  −4.0  −5.0  LS change dyskinesia forthe treatment — −11%  −26% −30%  (A-P)/base groups versus placebo ONtime with 6.1 6.3 4.5 5.1 Baseline Decrease in ON time with troublesome−1.4  −2.7  −3.2  −4.2  LS change troublesome dyskinesia for thedyskinesia (hours) — −21%  −40% −55%  (A-P)/base treatment groups versusplacebo OFF time (hours) 3.2 2.7 4.3 2.2 Baseline Decrease in OFF timefor 0.3 −1.0  −0.6  0.4 LS change the 260 mg and 340 mg — −48%  −21%  5%(A-P)/base treatment groups versus placebo CGIC** Mean value at week 8Improvement in CGIC 0.8 1.4 1.9 1.3 Mean for all treatment — 75% 138%62% (A-P)/P** groups versus placebo *Baseline is the mean value at thestudy baseline for the treatment group. LS mean change is the leastsquares change in the value at the 8 week time point for the treatmentgroup. (A-P)/base equals (the LS mean change for the active group lessthe LS mean change for the placebo group) divided by the mean baselinevalue for the active group multiplied by 100%. **The Clinician’s GlobalImpression of Change (CGIC) is assessed on a 7 point scale (+3 “MarkedImprovement” to −3 “Marked worsening”) based on a response to thefollowing question: “Considering your observations and impression of thesubject’s clinical status related to overall Parkinson’s disease,including but not limited to Levodopa-induced Dyskinesias, how much hasthe subject changed between baseline and this visit?”

ON time without dyskinesia increased in all groups from baseline to 8weeks, however the increase in ON time without dyskinesia for thetreatment groups, including the 340 mg treatment group was larger thanthe increase for the placebo group.

The Clinician's Global Impression of Change in Overall PD symptoms issummarized in the table below. The results for the MITT population showa statistically significant improvement for the 340 mg treatment group,but not for the other groups.

TABLE 9 260 mg 340 mg 420 mg Visit: Day 57/ Visit 8 Placebo ADS−5102ADS−5102 ADS−5102 Category (N = 22) (N = 19) (N = 20) (N = 19) MarkedImprovement 1 (4.5) 2 (10.5) 7 (35.0) 4 (21.1) Moderate Improvement  6(27.3) 8 (42.1) 8 (40.0) 6 (31.6) Minimal Improvement  4 (18.2) 5 (26.3)1 (5.0)  5 (26.3) No Change 10 (45.5) 3 (15.8) 4 (20.0) 2 (10.5) MinimalWorsening 1 (4.5) 1 (5.3)  0 0 Moderate Worsening 0 0 0 2 (10.5) MarkedWorsening 0 0 0 0 P-value¹ 0.1042 0.0036 0.2158 ¹The p-value is from theCochran-Mantel-Haenszel mean score test (using equally spaced scores).

The CGI-C results indicated that 75% of patients in the 340 mg dosegroup had a moderate to marked improvement in their clinical status(related to overall PD, including but not limited to LID) at week 8,versus 32% of placebo patients. Additional summaries of the analysis areprovided in the figures. Additional discussion of this data may be foundin US20150087721.

While certain embodiments of the present disclosure have been shown anddescribed herein, such embodiments are provided by way of example only.Numerous variations, changes, and substitutions will now occur to thoseskilled in the art without departing from the disclosure. It should beunderstood that various alternatives to the embodiments of thedisclosure described herein may be employed in practicing the methods orpreparing the compositions as described herein. All references citedherein are incorporated herein by reference in their entirety.

Example 7: A Randomized, Double-Blind, Placebo-Controlled Study of theEfficacy and Safety of Two Formulations of Amantadine Extended ReleaseOral Capsules for the Treatment of Levodopa-Induced Dyskinesia inParkinson's Disease

Study Objectives: This study is designed to evaluate the efficacy of twodifferent formulations of Amantadine Extended Release (ER) oral capsulesdosed once nightly at nighttime for the treatment of levodopa-induceddyskinesia (LID) in subjects with Parkinson's Disease (PD). In addition,the study is designed to demonstrate the safety and tolerability of twoformulations of Amantadine ER oral capsules dosed once nightly for thetreatment of LID in subjects with PD. Study design: This is amulti-center, randomized, double-blind, placebo-controlled, 3-armparallel group study of Amantadine ER formulations in patients with PDwho have LID. Consenting subjects who meet eligibility criteria arerandomized 1:1:1 to receive one of the following 3 treatments, eachadministered as once nightly, dosed at night:

-   -   Treatment A: Placebo,    -   Treatment B: 340 mg Amantadine Hydrochloride ER (Type C),    -   Treatment C: 340 mg Amantadine Hydrochloride ER (Type D)

Subjects who are randomized to Treatment B or C received, indouble-blind fashion, 170 mg Amantadine Hydrochloride ER of Type C orType D, respectively, once nightly during week 1, with an increase to340 mg Amantadine Hydrochloride ER of Type C or Type D, respectively,once nightly at the beginning of week 2. Dosing for all groups iscontinued at the nominal dose through week 8.

Following completion of the baseline visit and randomization, subjectsreturn to the clinic after 1, 2, 4, 6, and 8 weeks of dosing, with afollow-up visit 14 days following the last dose of study drug. Studyvisits and assessments are scheduled during the hours between 10 amthrough 4 pm. A set of two 24-hour diaries are completed during 48 hoursprior to randomization and 48 hours prior to selected study visits. Thediary is used to score five different conditions in 30-minute intervals:Sleep, OFF, ON without dyskinesias, ON with nontroublesome dyskinesias,ON with troublesome dyskinesias.

Blood samples are collected at selected study visits for determinationof amantadine plasma concentrations, and evaluation of steady-statepopulation pharmacokinetics. Subject participation during the study isup to 12 weeks including a 2-week (maximum) screening period, 8-week(maximum) treatment period, and a 2-week follow-up period. Subjectsunable to tolerate their assigned study drug assignment permanently arediscontinued study drug and are followed for safety through 2 weeksfollowing the last dose of study drug.

Patient Eligibility Criteria: Subjects are eligible to take part in thestudy if they met the inclusion and do not meet the exclusion criteria.Selected key criteria are as follows:

Inclusion Criteria:

-   -   Male or female adults    -   Between 30 and 85 years of age, inclusive    -   Ambulatory or ambulatory-aided (e.g. walker or cane) ability        while ON, such that the subject can could complete study        assessments    -   Knowledgeable and reliable caregiver/study partner, if        appropriate, to accompany the subject to study visits and assist        in completion of study instruments, as needed and allowed    -   Sign a current IRB/IEC-approved informed consent form    -   Following diary training, the subject is willing and able to        understand and complete the 24-hour PD home diary        (caregiver/study partner assistance allowed)    -   Parkinson's Disease, complicated per UK Parkinson's Disease        Society (UKPDS) Brain Bank Clinical Diagnostic Criteria    -   On a stable regimen of antiparkinson's medications, including        levodopa, for at least 30 days prior to screening, with any        levodopa administered not less than three times daily, and        willing to continue the same doses and regimens during study        participation    -   A score of at least 2 on part IV, item 4.2 (functional impact of        dyskinesias) of the Unified Parkinson's Disease Rating Scale        (MDS-UPDRS), at screening and at Day 1 (baseline)    -   Using the 48-hour PD home diaries completed just prior to Day 1        (baseline), at least 2 half-hour time periods between 10 am and        4 pm of each 24-hour period are indicated as “ON with        troublesome dyskinesia”

Key Exclusion Criteria:

-   -   History of deep brain simulation; history of exclusively        diphasic, off state, myoclonic or akathetic dyskinesia without        peak dose dyskinesia    -   History of other neurological disease that, in the opinion of        the investigator, would affect cognition or motor function,        including, but not limited to Alzheimer's dementia, Huntington's        disease, Lewy body dementia, frontotemporal dementia,        corticobasal degeneration, progressive supranuclear palsy,        multiple system atrophy, motor or sensory dysfunction secondary        to stroke or brain trauma, or multi-infarct dementia with        lacunae.    -   Presence of cognitive impairment, as evidenced by a Mini-mental        State Examination (MMSE) score of less than 24 during screening.    -   Presence of an acute or chronic major psychiatric disorder        (e.g., Major Depressive Disorder) or symptom (e.g.,        hallucinations, agitation, paranoia) that, in the opinion of the        investigator, would affect the subject's ability to complete        study assessments    -   History of sensory impairments (e.g., hearing, vision) that, in        the opinion of the investigator, would impair the subject's        ability to complete study assessments    -   History of alcohol or drug dependence or abuse within 2 years        prior to screening    -   History of seizures within 2 years prior to screening    -   History of stroke or TIA within 2 years prior to screening    -   History of myocardial infarction, or NYHA Functional        Classification of Heart Failure Class 3 or 4 within 2 years        prior to screening    -   History of cancer within 5 years prior to screening, with the        following exceptions: adequately treated non-melanomatous skin        cancers, localized bladder cancer, non-metastatic prostate        cancer or in situ cervical cancer    -   Any of the following laboratory test results at screening:        Hemoglobin<10 g/dL, WBC<3.0×10⁹/L, Neutrophils<1.5×10⁹/L,        Lymphocytes<0.5×10⁹/L, Platelets<100×10⁹/L, Hemoglobin A1C>9%,        or Aspartate aminotransferase (AST) and/or alanine        aminotransferase (ALT)>2 times the upper limit of normal    -   Estimated GFR<50 mL/min/1.73 m² by Modification of Diet in Renal        Disease (MDRD) equation    -   Any clinically significant ECG abnormalities, including any        findings of abnormal ventricular conduction of rhythm other than        isolated PVCs or first degree AV block    -   Inability to swallow oral capsules, or a history of        gastrointestinal malabsorption that would preclude the use of        oral medication

Study Endpoints: The primary efficacy endpoint is the change frombaseline to week 8 in the Unified Dyskinesia Rating Scale (UDysRS) totalscore. Key secondary endpoints include change from baseline to week 8:

-   -   Total Objective Score (III, IV) of the UDysRS    -   ON time without troublesome dyskinesia (ON without dyskinesia        plus ON with non-troublesome dyskinesia), based on the PD home        diary    -   ON time with troublesome dyskinesia, based on a standardized PD        home diary    -   Total ON time with dyskinesia (non-troublesome and troublesome)    -   Total OFF time    -   Unified Parkinson's Disease Rating Scale (MDS-UPDRS), combined        score (Parts I, II and III)    -   Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part IV,        items 4.1 (time spent with dyskinesias) and 4.2 (functional        impact of dyskinesias)    -   Unified Parkinson's Disease Rating Scale (MDS-UPDRS), individual        part scores (I, II, III, and IV)    -   Clinician's Global Impression of Change in overall PD symptoms,        determined by a question completed by the investigator    -   Health-related Quality of Life as measured by a PD-specific        HRQoL instrument, the PDQ-39    -   Fatigue as measured by the Fatigue Severity Scale (FSS). This        scale includes 9 questions that are completed by the patient        using a rating scale from 1 (strongly disagree) to 7 (strongly        agree). Safety, including adverse events, safety-related study        drug discontinuations, vital signs, and laboratory tests.

The following mixture of traditional and new scales have been selectedfor this study:

-   -   Unified Dyskinesia Rating Scale (UDysRS) was used for primary        outcome measure. This scale has four parts, and a total possible        score of 104:    -   I: Historical Disability (patient perceptions) of On-Dyskinesia        impact    -   II: Historical Disability (patient perceptions) of Off-Dystonia        impact    -   III: Objective Impairment (dyskinesia severity, anatomic        distribution, and type, based on 4 observed activities)    -   IV: Objective Disability based on Part III activities    -   ON time without troublesome dyskinesia, based on a standardized        Parkinson's disease home diary.    -   MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part        IV, items 4.1 (duration of dyskinesias: 0=none, 4=76-100% of the        waking day) and 4.2 (disability of dyskinesias: 0=not disabling,        4=completely disabling) was a secondary outcome measure.

Statistical Methods

Efficacy Analyses: The efficacy analysis population includes allrandomized and dosed subjects who provide at least one post-baselineefficacy assessment, and meet prespecified entry criteria. Unlessspecified otherwise, all efficacy endpoints are analyzed using analysisof covariance (ANCOVA) models with the change from baseline to Week 8 asthe dependent variable, treatment group as a factor, and the baselinevalue of the corresponding endpoint as a covariate. These models areused for both pair-wise comparisons between each amantadine ER dosegroup versus placebo. For the efficacy endpoint of UDysRS score, theprimary analysis compares each amantadine ER group (Treatment B andTreatment C) to the placebo group using a two-sided test at the 5% levelof significance. Similarly, for the efficacy endpoint of UDysRS score,the primary analysis compares the amantadine ER Treatment B to TreatmentC using a two-sided test at the 5% level of significance.

The secondary endpoints are analyzed using the same types of ANCOVAmodels as described for the primary endpoint, except for CGIC which is aCMH analysis. All secondary comparisons between treatment groups areperformed using two-sided tests at the 5% level of significance. A lastobservation carried forward (LOCF) approach is utilized for missingdata. The primary efficacy analysis is repeated for the per-protocolpopulation, a subset of the efficacy analysis population who provideweek 8 efficacy assessments. The CGI is a CMH analysis.

-   -   Results: selected study results are shown in the table below.

TABLE 10 Instruments Effect Unified Dyskinesia Rating Reduction in totalUDysRS greater for the treatment groups than placebo. Scale (UDysRS)total score Comparable reduction in total UDysRS for Treatment B andTreatment C Unified Dyskinesia Rating Reduction in UDysRS totalObjective greater for the treatment groups than Scale (UDysRS) objectiveplacebo. total (parts III, IV) Comparable reduction in UDysRS totalObjective for Treatment B and Treatment C Unified Parkinson’s Reductionin MDS-UPDRS Part IV greater for the treatment groups than DiseaseRating Scale placebo. (UPDRS, MDS revision), Comparable reduction inMDS-UPDRS Part IV for Treatment B and Part IV Treatment C ON timewithout Increase in ON time without troublesome dyskinesia for thetreatment groups troublesome dyskinesia versus placebo (hours)Comparable increase in ON time without troublesome dyskinesia vs.Placebo for Treatment B and Treatment C ON time with dyskinesia Decreasein ON time with dyskinesia for the treatment groups vs. Placebo. (hours)Comparable decrease in ON time with dyskinesia vs. Placebo for TreatmentB and Treatment C ON time with troublesome Decrease in ON time withtroublesome dyskinesia vs. Placebo for the treatment dyskinesia (hours)groups. Comparable decrease in ON time with troublesome dyskinesia vs.Placebo for Treatment B and Treatment C OFF time (hours) Decrease in OFFtime for the treatment groups vs. Placebo Comparable decrease in OFFtime for the vs. Placebo for Treatment B and Treatment C CGIC**Improvement in CGIC vs. Placebo for treatment groups Comparableimprovement in CGIC vs. Placebo for Treatment B and Treatment C **TheClinician’s Global Impression of Change (CGIC) is assessed on a 7 pointscale (+3 “Marked Improvement” to -3 “Marked worsening”) based on aresponse to the following question: “Considering your observations andimpression of the subject’s clinical status related to overallParkinson’s disease, including but not limited to Levodopa-inducedDyskinesias, how much has the subject changed between baseline and thisvisit?”

ON time without dyskinesia is expected to increase more in Treatment Band Treatment C groups from baseline to 8 weeks than any change forTreatment A (Placebo).

The Clinician's Global Impression of Change in Overall PD symptoms isexpected to show improvement for Treatment B and Treatment C groups atthe end of the treatment period. The results for Treatment B andTreatment C is expected to be similar.

Safety results: Adverse events are recorded throughout the study andcoded MedDRA classifications. Gastrointestinal disorders are expected tobe lowest for Treatment Group A (Placebo). The frequency ofgastrointestinal disorders is expected to be lower for Treatment C thanfor Treatment B. Gastrointestinal disorders for Treatment C are expectedto be less than the 19.5% rate observed by Hayden (1981) for dailyadministration of 300 mg amantadine hydrochloride in divided doses. Thefrequency of sleep related adverse events is expected to be similaracross the groups and not statistically significant from one group toanother.

Example 8: Approaches to Reducing Residual Solvent

For amantadine ER formulations manufactured in a manner similar to thatdescribed in Example 1 (Type C) described above, various approaches toreducing the amount of residual solvent were attempted.

Batches of amantadine extended release coated pellet formulation wereprepared using a ratio of isopropyl alcohol (IPA) to purified water of40:60, 60:40 and 95:5 w/w in the drug coating, seal coating, and ERcoating dispersions, respectively. Changes in drug coating processparameters were made in an attempt to reduce the level of residualsolvent. These changes included intermittent drying at different timesduring drug coating, drying at a higher temperature (80° C.), drying ata lower humidity, increasing drying time, and increasing in product(drug coating) temperature during coating. None of these changes inprocess led to significant reduction in residual IPA.

Intermediate drying during drug coating: One approach that was tried toreduce residual solvent was drying the pellets at intermediate stagesduring the coating process. FIG. 4 presents a schematic of the controlprocedure for Batch 166, without intermediate drying, while FIG. 5presents a schematic of intermediate drying procedure for Batch 167, inwhich the pellets were dried at four points during the drug-coatingprocess. In these schematics, the amount of drug coating added ispresented as % w/w compared to the initial weight of the uncoatedpellets. At various points during these two procedures, samples werewithdrawn and the amount of IPA present evaluated (ppm). The residualIPA present at different times during the intermediate drying process ispresented in the schematics of FIG. 4 and FIG. 5, the graph of FIG. 6,and in Table 11 below.

Terminal drying of drug-coated pellets: Another approach that wasattempted was to change the time, temperature, and/or humidity used whendrying the fully coated pellets. Referring to FIG. 4 (the batch that didnot go through intermediate drying), the fully coated pellets weredivided into two fractions and dried at 50° C. at ambient or highhumidity. Referring to FIG. 5 (intermediate drying), the fully coatedpellets were divided into two fractions and dried at 50° C. at ambientor high humidity. Samples were taken at 30 or 90 minutes and theresidual IPA evaluated (ppm). The effect of these different terminaldrying procedures on the residual IPA level is presented in FIG. 7 andTable 11 below.

Increased temperature of drug coating product during coating: Table 11also includes data from Batch 168, in which the temperature of the drugcoating material was increased to 48-51° C. during the coating process.

TABLE 11 IPA content during and after drug coating Batch 166 Batch 167Batch 168 Product temperature (drug coating) 38-42° C. 38-42° C. 48-51°C. Intermittent drying No Yes No IPA Level 25% w/w drug coated, undried3258 ppm 2645 ppm — 25% w/w drug coated, dried at — 2783 ppm — 50° C.for 30 min 50% w/w drug coated, undried 5469 ppm 4640 ppm 3630 ppm 50%w/w drug coated, dried at — 4484 ppm — 50° C. for 30 min 150% w/w drugcoated, undried 9862 ppm 9357 ppm 7338 ppm 150% w/w drug coated, driedat — 9327 ppm — 50° C. for 30 min 300% w/w drug coated, undried 12874ppm 12028 ppm 8698 ppm 300% w/w drug coated, dried at — 12138 ppm — 50°C. for 30 min 484.4% w/w drug coated, undried 13857 ppm 14006 ppm 10158ppm 484.4% w/w drug coated, dried for 13535 ppm — 9786 ppm 30 min at 50°C. at ambient RH

In addition to evaluating IPA content at different points during andafter the drug coating process as described above, the amount of IPApresent was also evaluated in batches at different points after applyingand drying the seal coating and the extended release coating. Table 12summarizes these data.

TABLE 12 IPA content at each coating stage (At each stage, pooled samplebefore sieving was used) Drying Batch Batch Batch Batch Stage Time09-001 9130 9131 9165 Drug  0 min — 9924 ppm 8587 ppm 8201 ppm Coating30 min — 9523 ppm 8814 ppm 8057 ppm 60 min 8746 ppm 8607 ppm 8705 ppm8376 ppm Seal  0 min — 9943 ppm 9454 ppm 8929 ppm Coating 30 min 8746ppm 9782 ppm 8832 ppm 8992 ppm 60 min 8397 ppm 9151 ppm 8220 ppm 9757ppm Extended  0 min 6653 ppm 8026 ppm 7814 ppm — Release 30 min 6385 ppm8019 ppm 7705 ppm — Coating 60 min 6273 ppm 7863 ppm 7882 ppm 7191 ppm

Example 9: Study to Assess the Efficacy and Safety of Amantadine Hcl ERin MS Patients with Walking Impairment

A 3-arm, multicenter, double-blind, placebo-controlled, randomized studywill be used to assess the efficacy and safety of amantadine extendedrelease capsules in Multiple Sclerosis patients with walking impairment.Approximately 570 subjects are to be enrolled in the Single-BlindPlacebo Run-In Period to ensure that 540 subjects complete theSingle-Blind Placebo Run-In Period and are eligible to be randomizedinto the Double-Blind Treatment Period. This study will be carried outusing an extended release amantadine hydrochloride formulation with lowresidual organic solvent, similar to the one described in Example 2(Type D).

Primary Objective:

-   -   To evaluate the efficacy of 274 mg amantadine (as 340 mg        amantadine HCl ER) in subjects with multiple sclerosis (MS) with        walking impairment as measured by the Timed 25-foot Walk (T25FW,        feet/second) at Week 16.

Secondary Objectives:

-   -   Key: To evaluate the efficacy of 274 mg amantadine (as 340 mg        amantadine HCl ER) and 137 mg amantadine (as 170 mg amantadine        HCl ER) in subjects with MS and walking impairment as measured        by the T25FW, Timed Up and Go (TUG) test, and the 2-Minute Walk        Test (2MWT) at Week 16.    -   Supportive: To evaluate the efficacy of the two dosages in        subjects with MS and walking impairment as measured by the        T25FW, the TUG, and the 2MWT across all study visits. To        evaluate the efficacy in subjects with MS and walking impairment        as measured by the Multiple Sclerosis Walking Scale-12        (MSWS-12).    -   Safety: To evaluate the safety and tolerability of the two        dosages in subjects with MS and walking impairment.

Study Design: This will be a multicenter, 3-arm, randomized,placebo-controlled, double-blind, parallel-group study of amantadineextended release [ER] capsules in MS patients with walking impairment,incorporating a Single-Blind Placebo Run-In Period prior torandomization, and forced up-titration for the high-dose group.Eligibility for inclusion in this study will require all subjects to beon a stable medication regimen for at least 30 days prior to screening,and to continue the same dosing regimen for the duration of their studyparticipation. Subjects may not have been treated with dalfampridinewithin 30 days prior to screening. Consented subjects who complete theup to 3-week screening period will undergo a 4-week Single-Blind PlaceboRun-In Period during which subjects will receive placebo as 2 capsulesonce daily at bedtime. Subjects who complete the Single-Blind PlaceboRun-In Period and continue to meet study eligibility criteria will berandomized with equal probability to 1 of 3 treatment groups: placebo oramantadine at 137 mg or 274 mg per dose (as 170 mg or 340 mg amantadineHCl, respectively). Study drugs will be administered as 2 capsules oncedaily at bedtime.

-   -   Subjects who are randomized to placebo will receive placebo        capsules throughout the 12-week Double-Blind Treatment Period.    -   Subjects who are randomized to 137 mg amantadine will receive        137 mg of amantadine (as 170 mg amantadine HCl) throughout the        Double-Blind Treatment Period.    -   Subjects who are randomized to 274 mg amantadine will receive        137 mg for the first week, 205.5 mg for the second week, and 274        mg for the remainder of the 12-week Double-Blind Treatment        Period (as the equivalent amount of amantadine HCl).    -   During the Double-Blind Treatment Period, subjects will return        to the clinic for safety and efficacy assessments at Weeks 6, 8,        12, and 16. In addition, telephone visits for safety assessments        will be conducted at Weeks 5 and 7.

Subjects who complete the study through the Week 16 visit will beeligible to enter an optional open-label extension (OLE) study. Subjectswho withdraw from the study prior to completion of the Week 16 visitwill have an early termination visit that includes safety follow-up andefficacy assessments. Subjects who complete 12 weeks of double-blindtreatment and elect not to participate in the OLE study will have afinal post-treatment safety and efficacy assessment 2 weeks after theirWeek 16 visit. The end of study (EOS) is defined as when a subjectcompletes the Week 16 visit (if electing to enter the OLE study) or thesafety follow-up visit (if electing not to enter the OLE study).

All study visits and efficacy assessments should be scheduled to occurat approximately the same time of day for each individual subject. Tothe extent practicable, study visits and efficacy assessments should bescheduled to occur when a subject is not likely to be experiencing acuteside effects from a concomitant medication (e.g., flu-like side effectsfollowing interferon-beta injection). Efficacy assessments should beconducted in following sequence: MSWS-12; T25FW; TUG; 2MWT. Subjectsusing an assistive device during the walking assessments at Screeningshould use the same assistive device for all subsequent walking tests.Each subject's efficacy assessment should be performed by the sameclinical rater, if possible.

Adverse events (AEs) and concomitant medications will be recordedbeginning with the first dose of study drug during the Single-BlindPlacebo Run-In Period and continuing through the last study visit.

Inclusion Criteria:

-   1. Signed a current IRB-approved informed consent form-   2. Male or female subjects between 18 and 70 years of age,    inclusive, at the time of Screening-   3. Confirmed diagnosis of MS according to the 2017 McDonald criteria    (Thompson et al., 2017)-   4. Current medication regimen must be stable for at least 30 days    prior to screening, and subject must be willing to continue the same    dosing regimen for the duration of study participation-   5. Maximum Expanded Disability Status Scale (EDSS) score during    screening of 6.5-   6. Sufficient ambulatory ability (ambulatory aids acceptable if used    consistently) to complete two trials of the Timed 25-Foot Walk    (T25FW) at the screening visit, with the two trials completed within    5 minutes of each other in accordance with the specific instructions    provided by the National MS Society Functional Composite Manual-   7. Stable physical activity level (inclusive of prescribed physical    therapy) for at least 30 days prior to screening and willing to    continue without change for the duration of study participation    A score on each of two completed screening T25FW tests between 8 and    45 seconds, inclusive

Criteria:

-   1. Documented inability to tolerate amantadine-   2. History of hypersensitivity or allergic reaction to amantadine,    rimantadine, or memantine, or to any of the excipients used in the    study drug capsules-   3. Clinically significant MS relapse with onset less than 30 days    prior to screening-   4. Presence of neurologic dysfunction or medical condition, the    severity of which, in the judgement of the investigator, would    preclude the ability to perform walking tests safely-   5. Receipt of systemic corticosteroids (intravenous [IV] or oral) or    ACTHAR gel within 30 days prior to screening-   6. Receipt of dalfampridine (or any 4-aminopyridine or    2,4-diaminopyridine preparation) or amantadine within 30 days prior    to screening-   7. History of other neurological or medical condition that, in the    opinion of the investigator, would affect study outcome assessments-   8. History of seizures within 3 years prior to screening-   9. History of hallucinations (visual, auditory, or any other type)    within 3 years prior to screening-   10. History of bipolar disorder, schizophrenia, or psychosis,    regardless of treatment-   11. For subjects with a history of major depressive disorder, the    presence of active depressive symptoms that, in the opinion of the    investigator, would affect the subject's ability to complete study    assessments, or which would not be in the subject's best interest to    participate in the study-   12. History of suicide attempt-   13. History of suicidal ideation within 3 years of screening, or    presence of suicidal ideation at screening, as detected by the    Columbia Suicidality Scale (C-SSRS)-   14. History of cognitive impairment sufficient, in the clinical    judgement of the investigator, to affect the subject's ability to    consent or complete study assessments, or to render it not in the    subject's best interest to participate in the study-   15. History of alcohol or substance dependence or abuse within 2    years prior to screening-   16. History of stroke, transient ischemic attack (TIA), or    myocardial infarction (MI) within 2 years prior to screening-   17. History of cancer within 5 years prior to screening, with the    following exceptions: adequately treated non-melanomatous skin    cancers, localized bladder cancer, non-metastatic prostate cancer,    in situ cervical cancer, or other definitively treated cancer that    is considered cured-   18. Presence of orthostatic hypotension at screening: a decrease in    systolic blood pressure (at least 20 mm Hg) or diastolic blood    pressure (at least 10 mm Hg) within 3 minutes of the subject    standing up, compared to pressures obtained while sitting-   19. Any laboratory test results outside of the central laboratory's    normal range at screening that are assessed by the investigator to    be clinically significant. Documentation by the investigator of    clinical significance or insignificance must accompany out of range    laboratory test results at screening-   20. Aspartate aminotransferase (AST) and/or alanine aminotransferase    (ALT) screening laboratory results>2 times the upper limit of normal-   21. Estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m²    (per Modification of Diet in Renal Disease [MDRD] calculation)-   22. Inability to swallow oral capsules, or a history of    gastrointestinal malabsorption that would preclude the use of oral    medication-   23. If female, is pregnant or lactating-   24. If a sexually active female, is not surgically sterile or at    least 2 years post-menopausal, or does not agree to utilize a highly    effective hormonal method of contraception (an IUD, or vasectomized    male partner is also acceptable), in combination with a barrier    method, from screening through at least 4 weeks after the completion    of study treatment. If a sexually active male, does not agree to    utilize condoms from screening through at least 4 weeks after the    completion of study treatment.-   25. Received live attenuated influenza vaccine within 2 weeks prior    to randomization or planning to receive live attenuated influenza    vaccine during the duration of the study (amantadine may interfere    with the efficacy of live attenuated vaccine)-   26. Current treatment with medications that may affect urinary pH:    carbonic anhydrase inhibitors, sodium bicarbonate, urinary    acidification agents, quinine, quinidine, triamterene, or    trimethoprim-   27. Treatment with an investigational drug or device within 30 days    prior to screening-   28. Treatment with an investigational biologic within 6 months or 5    half-lives, whichever is longer, prior to screening-   29. Current participation in another clinical trial-   30. Prior or current participation in an Adamas clinical trial-   31. Planned elective surgery, with the exception of minor    dermatological procedures, during study participation

Investigational Product, Dosage and Mode of Administration: All subjectsare to continue their current (prior to screening visit) MS medicationsand regimens, without change, for the duration of their studyparticipation, to the extent compatible with good neurological care.Consented subjects who complete screening and the Single-Blind PlaceboRun-In Period and meet study eligibility criteria will be randomizedwith equal probability to 1 of 3 treatment groups: placebo, 137 mgamantadine (as 170 mg amantadine HCl), or 274 mg amantadine (as 340amantadine HCl). Amantadine HCl ER capsules will be administered orally,as 2 capsules once daily at bedtime for the 12-week Double-BlindTreatment Period. The dosing regimens for the 2 active treatment armsare:

-   -   137 mg/d (1×137 mg capsule+1 placebo capsule) for 12 weeks for        the 137 mg amantadine group (as corresponding amounts of        amantadine HCl)    -   137 mg/d for 1 week (1×137 mg capsule+1 placebo capsule),        followed by 205.5 mg/d (1×137 mg capsule+1×68.5 mg capsule) for        1 week, followed by 274 mg/d (2×137 mg capsules) for 10 weeks        for the 274 mg amantadine group (as corresponding amounts of        amantadine HCl)

Reference Therapy, Dosage and Mode of Administration: Placebo capsules(indistinguishable from amantadine capsules) will be administered orallyas 2 capsules once daily at bedtime for the 4-week Single-Blind PlaceboRun-In Period for all subjects and for the 12-week Double-BlindTreatment Period for subjects randomized to the placebo arm.

Duration of Treatment: Maximum duration of subject participation is upto approximately 21 weeks and will include a 3-week (maximum) screeningperiod, 4-week Single-Blind Placebo Run-In Period, a 12-weekDouble-Blind Treatment Period for all subjects, and a 2-weekpost-treatment safety follow-up period for subjects who choose not toparticipate in the OLE study.

Criteria for Evaluation:

-   -   Primary Efficacy Measure: T25FW (measured in seconds but        calculated to a feet/sec measurement)    -   Secondary Efficacy Measures: TUG (seconds), 2MWT (meters), and        MSWS-12    -   Safety Measures: Adverse events (AEs), clinical laboratory        evaluations (hematology, clinical chemistry, urinalysis, serum        pregnancy tests for females of child bearing potential), vital        signs, and Columbia-Suicide Severity Rating Scale (C-SSRS)

While certain embodiments of the present disclosure have been shown anddescribed herein, such embodiments are provided by way of example only.Numerous variations, changes, and substitutions will now occur to thoseskilled in the art without departing from the disclosure. It should beunderstood that various alternatives to the embodiments of thedisclosure described herein may be employed in practicing methods orpreparing the compositions as described herein. All references citedherein are incorporated herein by reference in their entirety. Examplescontained within US20110189273 and US20150087721, both to Went, areincorporated herein in their entirety.

1. An oral pharmaceutical composition, comprising: a drug, wherein thedrug is amantadine or a pharmaceutically acceptable salt thereof, andwherein said oral pharmaceutical composition comprises from 50 mg to 500mg of the amantadine or an equivalent amount of the pharmaceuticallyacceptable salt thereof; and at least one excipient that modifies therelease of at least a portion of said drug; wherein said oralpharmaceutical composition has a dissolution profile of said drug whichshows (a) and/or (b): (a) (i) 0% to 10% in 2 hours, and (ii) 3% to 14%in 4 hours, and (iii) 23% to 40% in 6 hours, and (iv) not less than 80%in 12 hours; (b) (i) not more than 10% dissolution at 2 hours, and (ii)5% to 13% dissolution at 4 hours, and (iii) 20% to 44% dissolution at 6hours, and (iv) at least 80% dissolution at 12 hours; wherein thedissolution profile is determined with a USP Type 2 apparatus (paddles)at 50 rpm at 37.0±0.5° C. with 500 ml water as the dissolution medium;and wherein said oral pharmaceutical composition provides (i) a Tmax foramantadine of 11 to 19 hours, and (ii) an AUC_(0-inf) for amantadine of44 to 72 ng*hr/ml per mg of said drug, when said oral pharmaceuticalcomposition is dosed in healthy subjects of a single dose, humanpharmacokinetic study, wherein the subjects are dosed in the morningafter an overnight fast.
 2. The oral pharmaceutical composition of claim1, wherein said dissolution profile is (i) 0% to 9% in 2 hours, (ii) 3%to 14% in 4 hours, (iii) 24% to 40% in 6 hours, and (iv) not less than82% in 12 hours. 3-6. (canceled)
 7. The oral pharmaceutical compositionof claim 1, wherein the oral pharmaceutical composition has adissolution of 9% at 4 hours.
 8. The oral pharmaceutical composition ofclaim 1, wherein the oral pharmaceutical composition has a dissolutionof 31% at 6 hours.
 9. The oral pharmaceutical composition of claim 1,wherein the oral pharmaceutical composition has a dissolution of 61% at8 hours.
 10. The oral pharmaceutical composition of claim 1, wherein theoral pharmaceutical composition has a dissolution of 94% at 12 hours.11. The oral pharmaceutical composition of claim 1, wherein the oralpharmaceutical composition provides a pAUC₀₋₈ for amantadine that is 1.0to 2.0 ng*hr/ml per mg of said drug when dosed to healthy subjects of asingle dose, human pharmacokinetic study, wherein the subjects are dosedin the morning after an overnight fast.
 12. The oral pharmaceuticalcomposition of claim 11, wherein the oral pharmaceutical compositionprovides a pAUC₀₋₆ for amantadine that is 0.3 to 0.9 ng*hr/ml per mg ofsaid drug when dosed to healthy subjects of a single dose, humanpharmacokinetic study, wherein the subjects are dosed in the morningafter an overnight fast. 13-20. (canceled)
 21. The oral pharmaceuticalcomposition of claim 1, comprising from 100 mg to 450 mg of amantadine,or an equivalent amount of a pharmaceutically acceptable salt thereof.22. The oral pharmaceutical composition of claim 1, comprising from 120mg to 150 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof.
 23. The oral pharmaceuticalcomposition of claim 1, comprising 137 mg of amantadine, or anequivalent amount of a pharmaceutically acceptable salt thereof.
 24. Theoral pharmaceutical composition of claim 1, comprising from 260 mg to305 mg of amantadine, or an equivalent amount of a pharmaceuticallyacceptable salt thereof.
 25. The oral pharmaceutical composition ofclaim 24, comprising 274 mg of amantadine, or an equivalent amount of apharmaceutically acceptable salt thereof.
 26. The oral pharmaceuticalcomposition of claim 1, comprising one, two, three, or four unit dosageforms.
 27. The oral pharmaceutical composition of claim 1, comprisingone or two unit dosage forms.
 28. The oral pharmaceutical composition ofclaim 1, wherein the drug is a pharmaceutically acceptable salt ofamantadine.
 29. The oral pharmaceutical composition of claim 1, whereinthe drug is amantadine hydrochloride.
 30. The oral pharmaceuticalcomposition of claim 1, comprising less than 6000 ppm of organicsolvent.
 31. The oral pharmaceutical composition of claim 1, comprisingless than 2000 ppm of organic solvent. 32-34. (canceled)
 35. A method ofreducing levodopa-induced dyskinesia (LID) in a subject with Parkinson'sdisease in need thereof, comprising orally administering once daily tothe subject an oral pharmaceutical composition according to claim 1,wherein LID is reduced in the subject.
 36. The method of claim 35,wherein reducing LID comprises reducing the severity of dyskinesia. 37.The method of claim 35, wherein the reduction of LID is evaluated withthe Unified Dyskinesia Rating Scale (UDysRS).
 38. A method of increasingON time without troublesome dyskinesia in a subject with Parkinson'sdisease in need thereof, wherein the subject has levodopa-induceddyskinesia (LID), the method comprising orally administering once dailyto the subject an oral pharmaceutical composition according to claim 1.39. The method of claim 38, wherein the increase in ON time withouttroublesome dyskinesia is determined in a placebo controlled, doubleblind clinical study.
 40. A method of reducing OFF time in a subjectwith Parkinson's disease in need thereof, wherein the subject haslevodopa-induced dyskinesia (LID), the method comprising orallyadministering once daily to the subject an oral pharmaceuticalcomposition according to claim 1, wherein OFF time is reduced in thesubject.
 41. The method of claim 40, wherein the increase in OFF time isdetermined in a placebo controlled, double blind clinical study.
 42. Amethod of treating a hypokinetic disorder in a subject with MultipleSclerosis in need thereof, comprising orally administering once daily tothe subject an oral pharmaceutical composition according to claim
 1. 43.The method of claim 42, wherein the hypokinetic disorder is walkingimpairment. 44-76. (canceled)